Compositions useful for treating disorders related to kit

ABSTRACT

Compounds and compositions useful for treating disorders related to Kit are described herein.

CLAIM OF PRIORITY

This application claims priority to U.S. Ser. No. 62/032,731, filed Aug.4, 2014, the content of which is incorporated by reference in itsentirety.

BACKGROUND

The invention relates to compounds and compositions useful for treatingdisorders related to Kit.

The enzyme Kit (also called CD117) is a receptor tyrosine kinase (RTK)expressed on a wide variety of cell types. The Kit molecule contains along extracellular domain, a transmembrane segment, and an intracellularportion. The ligand for Kit is stem cell factor (SCF), whose binding tothe extracellular domain of Kit induces receptor dimerization andactivation of downstream signaling pathways. Kit mutations generallyoccur in the DNA encoding the juxtumembrane domain (exon 11). They alsooccur, with less frequency, in exons 7, 8, 9, 13, 14, 17, and 18.Mutations make Kit function independent of activation by SCF, leading toa high cell division rate and possibly genomic instability. Mutant Kithas been implicated in the pathogenesis of several disorders andconditions including including systemic mastocytosis, GIST(gastrointestinal stromal tumors), AML (acute myeloid leukemia),melanoma, and seminoma. As such, there is a need for therapeutic agentsthat inhibit Kit, and especially agents that inhibit mutant Kit.

SUMMARY OF THE INVENTION

The present invention provides compounds and compositions for treatingor preventing conditions such as mastocytosis by modulating the activityof Kit, such compounds having the structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X is selected from CH or N;

L is a bond, —(CR^(c)R^(c))_(n)—, —(CR^(c)R^(c))_(n)NR^(b)—,—NR^(b)(CR^(c)R^(c))_(n)—, —S(O)₂—, —S(O)—, —C(O)—, —OC(O)—, —C(O)O—,—(CR^(c)R^(c))_(n)—OC(O)—, —OC(O)—(CR^(c)R^(c))_(n)—,—(CR^(c)R^(c))_(n)—C(O)—, —C(O)—(CR^(c)R^(c))_(n)—,—NR^(b)C(O)(CR^(c)R^(c)), —C(O)NR^(b)—(CR^(c)R^(c)), where the twoR^(c)'s, together with the carbon to which they are attached, can form acarbocycle, —C(O)NR^(b)—(CR^(c)R^(b)),—(CR^(c)R^(c))—NR^(b)—(CR^(c)R^(c)), —NR^(b)C(S)—, —C(S)NR^(b)—,—NR^(b)C(O)—, —C(O)NR^(b)—, —NR^(b) S(O)₂, - or —S(O)₂NR^(b)—;

R¹ is alkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, or heterocyclylalkyl each of which issubstituted with 0-5 occurrences of R^(d);

R² is H, halo, aryl, alkenyl, heteroaryl, carbocyclyl, or heterocyclyl,wherein each of aryl, alkenyl, heteroaryl, carbocyclyl, and heterocyclylis substituted with 0-5 occurrences of R^(d);

R³ is H, alkyl, heteroalkyl, haloalkyl, haloalkoxyl, —OR^(c),—C(O)OR^(c), —C(O)NR^(a)R^(b), —(CR^(c)R^(c))—NR^(b)—(CR^(c)R^(c))—H,—NR^(a)R^(b), or cyano, wherein each of alkyl, heteroalkyl, haloalkyl,and haloalkoxyl is substituted with 0-5 occurrences of R^(d);

R^(a) and R^(b) are each independently H, alkyl, heteroalkyl, aryl,aralkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, wherein each ofalkyl, heteroalkyl, aryl, aralkyl, heterocyclyl, and heterocyclylalkylis substituted with 0-5 occurrences of R^(d); or R^(a) and R^(b)together with the nitrogen atom to which they are attached form aheterocyclyl substituted with 0-5 occurrences of R^(d);

R^(c) is H or alkyl;

each R^(d) is independently halo, heteroalkyl, haloalkyl, haloalkoxyl,alkyl, alkynyl, hydroxyalkyl, carbocyclyl, carbocyclylalkyl, aryl,aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, nitro, cyano,hydroxyl, —C(O)R^(a1), —OC(O)R^(a1), —C(O)OR^(a1), —SR^(a1),—S(O)₂R^(a1), —NR^(a1)R^(b1), —C(O) NR^(a1)R^(b1), —NR^(a1)S(O)₂R^(a1),or —OR^(a1); wherein each of heteroalkyl, haloalkyl, haloalkoxyl, alkyl,alkynyl, hydroxyalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heteroaryl, heterocyclyl, and heterocyclylalkyl is substituted with 0-5occurrences of R^(c1); or two R^(d) together with the atoms to whichthey are attached form a carbocyclyl or heterocyclyl, each optionallysubstituted with halo or alkyl;

R^(a1) and R^(b1) are each independently H, alkyl, aralkyl, carbocyclyl,heteroaryl, or heterocyclyl; or R^(a1) and R^(b1) together with thenitrogen atom to which they are attached form a heterocyclyl optionallysubstituted with halo or alkyl;

each R^(c1) is independently halo, —OR^(c2), —NR^(a1)R^(b1), alkyl,cyano, heteroalkyl, haloalkyl, haloalkoxyl, carbocyclyl,carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroaralkyl, aryl, or aralkyl;

R^(c2) is H or alkyl;

p and r are each independently 1 or 2; and

n is 1, 2, 3 or 4.

Compounds disclosed herein may be at least 5 times, but less than 10times, more active against the D816V mutation of Kit than againstwild-type Kit when measured in a biochemical assay; at least 10 times,but less than 25 times, more active against the D816V mutation of Kitthan against wild-type Kit when measured in a biochemical assay; atleast 25 times, but less than 50 times, more active against the D816Vmutation of Kit than against wild-type Kit when measured in abiochemical assay; at least 50 times, but less than 100 times, moreactive against the D816V mutation of Kit than against wild-type Kit whenmeasured in a biochemical assay; at least 100 times, but less than 500times, more active against the D816V mutation of Kit than againstwild-type Kit when measured in a biochemical assay; at least 500 times,but less than 1000 times, more active against the D816V mutation of Kitthan against wild-type Kit when measured in a biochemical assay; orgreater than 1000 times more active against the D816V mutation of Kitthan against wild-type Kit when measured in a biochemical assay.

Any of the compounds disclosed herein may be used to treat any of thediseases disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

“Aliphatic group” means a straight-chain, branched-chain, or cyclichydrocarbon group and includes saturated and unsaturated groups, such asan alkyl group, an alkenyl group, and an alkynyl group.

“Alkenyl” means an aliphatic group containing at least one double bond.

“Alkoxyl” or “alkoxy” means an alkyl group having an oxygen radicalattached thereto. Representative alkoxyl groups include methoxy, ethoxy,propyloxy, tert-butoxy and the like.

“Alkyl” refers to a monovalent radical of a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-12,1-10, or 1-6 carbon atoms, referred to herein as C₁-C₁₂ alkyl, C₁-C₁₀alkyl, and C₁-C₆ alkyl, respectively. Exemplary alkyl groups include,but are not limited to, methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,etc.

“Alkylene” refers to a divalent radical of an alkyl group, e.g., —CH₂—,—CH₂CH₂—, and CH₂CH₂CH₂—.

“Alkynyl” refers to a straight or branched hydrocarbon chain containing2-12 carbon atoms and characterized in having one or more triple bonds.Examples of alkynyl groups include, but are not limited to, ethynyl,propargyl, and 3-hexynyl. One of the triple bond carbons may optionallybe the point of attachment of the alkynyl substituent.

“Hydroxyalkyl” refers to an alkyl radical in which an alkyl hydrogenatom is replaced by a hydroxyl group. Hydroxyalkyl includes groups inwhich more than one hydrogen atom has been replaced by a hydroxyl group.

“Aromatic ring system” is art-recognized and refers to a monocyclic,bicyclic or polycyclic hydrocarbon ring system, wherein at least onering is aromatic.

“Aryl” refers to a monovalent radical of an aromatic ring system.Representative aryl groups include fully aromatic ring systems, such asphenyl, naphthyl, and anthracenyl, and ring systems where an aromaticcarbon ring is fused to one or more non-aromatic carbon rings, such asindanyl, phthalimidyl, naphthimidyl, or tetrahydronaphthyl, and thelike.

“Arylalkyl” or “aralkyl” refers to an alkyl moiety in which an alkylhydrogen atom is replaced by an aryl group. Aralkyl includes groups inwhich more than one hydrogen atom has been replaced by an aryl group.Examples of “arylalkyl” or “aralkyl” include benzyl, 2-phenylethyl,3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups.

“Halo” refers to a radical of any halogen, e.g., —F, —Cl, —Br, or —I.

“Haloalkyl” and “haloalkoxyl” refers to alkyl and alkoxyl radicals thatare substituted with one or more halo groups or with combinationsthereof. For example, the terms “fluoroalkyl” and “fluoroalkoxyl”include haloalkyl and haloalkoxyl groups, respectively, in which thehalo is fluorine.

“Heteroalkyl” refers to an alkyl radical, which has one or more skeletalchain atoms selected from an atom other than carbon, e.g., oxygen,nitrogen, sulfur, phosphorus or combinations thereof. A numerical rangemay be given, e.g. C₁-C₆ heteroalkyl which refers to the number ofcarbons in the chain, which in this example includes 1 to 6 carbonatoms. For example, a —CH₂OCH₂CH₃ radical is referred to as a “C₃”heteroalkyl. In some embodiments, a heteroalkyl refers to an alkyl,which has one or more skeletal chain carbon atoms replaced withnitrogen, e.g., a —CH₂NHCH₂CH₃ radical. Connection to the rest of themolecule may be through either a heteroatom or a carbon in theheteroalkyl chain.

“Carbocyclic ring system” refers to a monocyclic, bicyclic or polycyclichydrocarbon ring system, wherein each ring is either completelysaturated or contains one or more units of unsaturation, but where noring is aromatic.

“Carbocyclyl” refers to a monovalent radical of a carbocyclic ringsystem. Representative carbocyclyl radicals include cycloalkyl groups(e.g., cyclopentyl, cyclobutyl, cyclopentyl, cyclohexyl and the like),and cycloalkenyl groups (e.g., cyclopentenyl, cyclohexenyl,cyclopentadienyl, and the like).

“Carbocyclylalkyl” refers to an alkyl radical substituted with acarbocyclyl.

“Cycloalkyl” refers to a cyclic, bicyclic, tricyclic, or polycyclicnon-aromatic hydrocarbon groups having 3 to 12 carbons. Anysubstitutable ring atom can be substituted (e.g., by one or moresubstituents). The cycloalkyl groups can contain fused or spiro rings.Fused rings are rings that share a common carbon atom. Examples ofcycloalkyl moieties include, but are not limited to, cyclopropyl,cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl.

“Heteroaromatic ring system” refers to monocyclic, bicyclic orpolycyclic ring system wherein at least one ring is both aromatic andcomprises at least one heteroatom (e.g., N, O or S); and wherein noother rings are heterocyclyl (as defined below). In certain instances, aring which is aromatic and comprises a heteroatom contains 1, 2, 3, or 4ring heteroatoms in such ring.

“Heteroaryl” refers to a monovalent radical of a heteroaromatic ringsystem. Representative heteroaryl groups include ring systems where (i)each ring comprises a heteroatom and is aromatic, e.g., imidazolyl,oxazolyl, thiazolyl, triazolyl, pyrrolyl, furanyl, thiophenyl pyrazolyl,pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolizinyl, purinyl,naphthyridinyl, and pteridinyl; (ii) each ring is aromatic orcarbocyclyl, at least one aromatic ring comprises a heteroatom and atleast one other ring is a hydrocarbon ring or e.g., indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, pyrido[2,3-b]-1,4-oxazin-3-(4H)-one,5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl; and(iii) each ring is aromatic or carbocyclyl, and at least one aromaticring shares a bridgehead heteroatom with another aromatic ring, e.g.,4H-quinolizinyl.

“Heteroarylalkyl” and “heteroaralkyl” refers to an alkyl radicalsubstituted with a heteroaryl group.

“Heterocyclic ring system” refers to monocyclic, bicyclic and polycyclicring systems where at least one ring is saturated or partiallyunsaturated (but not aromatic) and comprises at least one heteroatom. Aheterocyclic ring system can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted.

“Heterocyclyl” refers to a monovalent radical of a heterocyclic ringsystem. Representative heterocyclyls include ring systems in which (i)every ring is non-aromatic and at least one ring comprises a heteroatom,e.g., tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl,piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl,dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl,and quinuclidinyl; (ii) at least one ring is non-aromatic and comprisesa heteroatom and at least one other ring is an aromatic carbon ring,e.g., 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl; and(iii) at least one ring is non-aromatic and comprises a heteroatom andat least one other ring is aromatic and comprises a heteroatom, e.g.,3,4-dihydro-1H-pyrano[4,3-c]pyridine, and1,2,3,4-tetrahydro-2,6-naphthyridine.

“Heterocyclylalkyl” refers to an alkyl group substituted with aheterocyclyl group.

“Cyano” refers to a —CN radical.

“Nitro” refers to —NO₂.

“Oxo” refers to an oxygen atom, which forms a carbonyl when attached tocarbon, an N-oxide when attached to nitrogen, and a sulfoxide or sulfonewhen attached to sulfur.

“Hydroxy” or “hydroxyl” refers to —OH.

“Substituted”, whether preceded by the term “optionally” or not, meansthat one or more hydrogens of the designated moiety are replaced with asuitable substituent. Unless otherwise indicated, an “optionallysubstituted” group may have a suitable substituent at each substitutableposition of the group, and when more than one position in any givenstructure may be substituted with more than one substituent selectedfrom a specified group, the substituent may be either the same ordifferent at each position. Combinations of substituents envisionedunder this invention are preferably those that result in the formationof stable or chemically feasible compounds. The term “stable”, as usedherein, refers to compounds that are not substantially altered whensubjected to conditions to allow for their production, detection, and,in certain embodiments, their recovery, purification, and use for one ormore of the purposes disclosed herein.

As used herein, the definition of each expression, e.g., alkyl, m, n,etc., when it occurs more than once in any structure, is intended to beindependent of its definition elsewhere in the same structure.

Certain compounds of the present invention may exist in particulargeometric or stereoisomeric forms. The present invention contemplatesall such compounds, including cis- and trans-isomers, R- andS-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemicmixtures thereof, and other mixtures thereof, as falling within thescope of the invention. Additional asymmetric carbon atoms may bepresent in a substituent such as an alkyl group. All such isomers, aswell as mixtures thereof, are intended to be included in this invention.

If, for instance, a particular enantiomer of compound of the presentinvention is desired, it may be prepared by asymmetric synthesis, or byderivation with a chiral auxiliary, where the resulting diastereomericmixture is separated and the auxiliary group cleaved to provide the puredesired enantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

Unless otherwise indicated, when a disclosed compound is named ordepicted by a structure without specifying the stereochemistry and hasone or more chiral centers, it is understood to represent all possiblestereoisomers of the compound, as well as enantiomeric mixtures thereof.

The “enantiomeric excess” or “% enantiomeric excess” of a compositioncan be calculated using the equation shown below. In the example shownbelow a composition contains 90% of one enantiomer, e.g., the Senantiomer, and 10% of the other enantiomer, i.e., the R enantiomer.

ee=(90−10)/100=80%.

Thus, a composition containing 90% of one enantiomer and 10% of theother enantiomer is said to have an enantiomeric excess of 80%.

The compounds or compositions described herein may contain anenantiomeric excess of at least 50%, 75%, 90%, 95%, or 99% of one formof the compound, e.g., the S-enantiomer. In other words such compoundsor compositions contain an enantiomeric excess of the S enantiomer overthe R enantiomer.

The compounds described herein may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example deuterium (²H), tritium (³H),carbon-13 (¹³C), or carbon-14 (¹⁴C). All isotopic variations of thecompounds disclosed herein, whether radioactive or not, are intended tobe encompassed within the scope of the present invention. In addition,all tautomeric forms of the compounds described herein are intended tobe within the scope of the invention.

The compound can be useful as the free base or as a salt. Representativesalts include the hydrobromide, hydrochloride, sulfate, bisulfate,phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate,laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate,lactobionate, and laurylsulphonate salts and the like. (See, forexample, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19.)

Certain compounds disclosed herein can exist in unsolvated forms as wellas solvated forms, including hydrated forms. In general, the solvatedforms are equivalent to unsolvated forms and are encompassed within thescope of the present invention. Certain compounds disclosed herein mayexist in multiple crystalline or amorphous forms. In general, allphysical forms are equivalent for the uses contemplated by the presentinvention and are intended to be within the scope of the presentinvention.

As used herein, the term “patient” refers to organisms to be treated bythe methods of the present invention. Such organisms preferably include,but are not limited to, mammals (e.g., murines, simians, equines,bovines, porcines, canines, felines, and the like), and most preferablyincludes humans.

As used herein, the term “effective amount” refers to the amount of acompound (e.g., a compound of the present invention) sufficient toeffect beneficial or desired results. An effective amount can beadministered in one or more administrations, applications or dosages andis not intended to be limited to a particular formulation oradministration route. As used herein, the term “treating” includes anyeffect, e.g., lessening, reducing, modulating, ameliorating oreliminating, that results in the improvement of the condition, disease,disorder, and the like, or ameliorating a symptom thereof.

Compounds

In one aspect, the invention provides a compound having structuralFormula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X is selected from CH or N;

L is a bond, —(CR^(c)R^(c))_(n)—, —(CR^(c)R^(c))_(n)NR^(b)—,—NR^(b)(CR^(c)R^(c))_(n)—, —S(O)₂—, —S(O)—, —C(O)—, —OC(O)—, —C(O)O—,—(CR^(c)R^(c))_(n)—OC(O)—, —OC(O)—(CR^(c)R^(c))_(n)—,—(CR^(c)R^(c))_(n)—C(O)—, —C(O)—(CR^(c)R^(c))_(n)—,—NR^(b)C(O)(CR^(c)R^(c)), —C(O)NR^(b)—(CR^(c)R^(c)), where the twoR^(c)'s, together with the carbon to which they are attached, can form acarbocycle, —C(O)NR^(b)—(CR^(c)R^(b)),—(CR^(c)R^(c))—NR^(b)—(CR^(c)R^(c)), —NR^(b)C(S)—, —C(S)NR^(b)—,—NR^(b)C(O)—, —C(O)NR^(b)—, —NR^(b) S(O)₂, - or —S(O)₂NR^(b)—;

R¹ is alkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, or heterocyclylalkyl each of which issubstituted with 0-5 occurrences of R^(d);

R² is H, halo, aryl, alkenyl, heteroaryl, carbocyclyl, or heterocyclyl,wherein each of aryl, alkenyl, heteroaryl, carbocyclyl, and heterocyclylis substituted with 0-5 occurrences of R^(d);

R³ is H, alkyl, heteroalkyl, haloalkyl, haloalkoxyl, —OR′, —C(O)OR^(c),—C(O)NR^(a)R^(b), —(CR^(c)R^(c))—NR^(b)—(CR^(c)R^(c))—H, —NR^(a)R^(b),or cyano, wherein each of alkyl, heteroalkyl, haloalkyl, and haloalkoxylis substituted with 0-5 occurrences of R^(d);

R^(a) and R^(b) are each independently H, alkyl, heteroalkyl, aryl,aralkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, wherein each ofalkyl, heteroalkyl, aryl, aralkyl, heterocyclyl, and heterocyclylalkylis substituted with 0-5 occurrences of R^(d); or R^(a) and R^(b)together with the nitrogen atom to which they are attached form aheterocyclyl substituted with 0-5 occurrences of R^(d);

R^(c) is H or alkyl;

each R^(d) is independently halo, heteroalkyl, haloalkyl, haloalkoxyl,alkyl, alkynyl, hydroxyalkyl, carbocyclyl, carbocyclylalkyl, aryl,aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, nitro, cyano,hydroxyl, —C(O)R^(a1), —OC(O)R^(a1), —C(O)OR^(a1), —SR^(a1),—S(O)₂R^(a1), —NR^(a1)R^(b1), —C(O) NR^(a1)R^(b1), —NR^(a1)S(O)₂R^(a1),or —OR^(a1); wherein each of heteroalkyl, haloalkyl, haloalkoxyl, alkyl,alkynyl, hydroxyalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heteroaryl, heterocyclyl, and heterocyclylalkyl is substituted with 0-5occurrences of R^(c1); or two R^(d) together with the atoms to whichthey are attached form a carbocyclyl or heterocyclyl, each optionallysubstituted with halo or alkyl;

R^(a1) and R^(b1) are each independently H, alkyl, aralkyl, carbocyclyl,heteroaryl, or heterocyclyl; or R^(a1) and R^(b1) together with thenitrogen atom to which they are attached form a heterocyclyl optionallysubstituted with halo or alkyl;

each R^(c1) is independently halo, —OR^(c2), —NR^(a1)R^(b1), alkyl,cyano, heteroalkyl, haloalkyl, haloalkoxyl, carbocyclyl,carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroaralkyl, aryl, or aralkyl;

R^(c2) is H or alkyl;

p and r are each independently 1 or 2; and

n is 1, 2, 3 or 4.

In some embodiments, the compound is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (IV):

or a pharmaceutically acceptable salt thereof.

The below Schemes are meant to provide general guidance in connectionwith preparing the compounds of the invention. One skilled in the artwould understand that the preparations shown in the Schemes can bemodified or optimized using general knowledge of organic chemistry toprepare various compounds of the invention. The following examples areintended to be illustrative, and are not meant in any way to belimiting.

Synthetic Protocol 1

Synthetic Protocol 1 is shown above. Pyrrolotriazinone (1) can becoupled (LG typically Cl, Br, I) to a boron, tin or zinc aryl,heteroaryl, alkenyl, alkyl reagent (2) via a palladium-mediated couplingreaction, e.g., Suzuki, Stille, Negishi coupling, to provide compound(3). Pyrrolotriazinone (3) can be transformed into pyrrolotriazine (4)via treatment with POCl₃ or other similar reagents. Pyrrolotriazine (4)can be substituted with azetidines (5 or 7) under nucleophilic aromaticsubstitution reaction conditions using an amine base such asdiisopropylethylamine (DIPEA) or triethylamine (TEA) in a polar solventsuch as dioxane to provide the piperazine-substituted pyrrolotriazine (6or 8). Azetidine (5) can be synthesized by reaction of A via an amidebond coupling to generate intermediate B followed by deprotection.Pyrrolotriazine (6) can also be achieved via an amide bond couplingreaction as the final synthetic step.

As shown below, Compounds 6 and 10 were prepared using SyntheticProtocol 1.

Synthesis of1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(4-methylbenzyl)azetidine-3-carboxamide(Compound 6)

Synthesis of4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazine

Synthesis of O-(diphenylphosphoryl)hydroxylamine

To a solution of hydroxylamine hydrochloride (7.3 g, 106 mmol, 2.5 eq)in water (12 mL) and dioxane (12 mL) was added a solution of NaOH (4.07g, 102 mmol, 2.4 eq) in water (12 mL), and the mixture was cooled to −5°C. in an ice/salt bath. A solution of diphenylphosphinic chloride (10 g,42 mmol, 1 eq) in dioxane (12 mL), precooled to below 10° C., wasrapidly added to the above solution in an ice/salt bath under vigorousstirring. After completion of the addition, the mixture was stirred foradditional 5 minutes in an ice/salt bath, then diluted with ice water(150 mL) and filtered. The filtration cake was washed with ice water,and lyophilized to give o-(diphenylphosphoryl)hydroxylamine (6.0 g,yield 61%) as a white solid. MS (ES+) requires: 233. found 234 [M+H]⁺;purity: 75%.

Synthesis of 1-amino-4-bromo-1H-pyrrole-2-carboxylic acid methyl ester

To a solution of 4-bromo-1H-pyrrole-2-carboxylic acid methyl ester (3.5g, 17.2 mmol, 1 eq) in DMF (120 mL) was added NaH (0.82 g, 20.6 mmol,1.2 eq) at 0° C., and the mixture was stirred at 0° C. for 1 h, followedby the addition of o-(diphenylphosphinyl)-hydroxylamine (6 g, 25.8mmol). The reaction mixture was stirred for another 1 h, thenneutralized with 20% NH₄Cl solution, and extracted with EA. The combinedorganic layers were washed with water and brine, dried over sodiumsulfate, filtered, and concentrated by evaporation. The residue waspurified by column chromatography on silica gel (PE/EA=4:1) to give1-amino-4-bromo-1H-pyrrole-2-carboxylic acid methyl ester (2.9 g, yield77%) as a light yellow solid. MS (ES+) requires: 218, 220. found 219,221 [M+H]⁺; purity: 97%.

Synthesis of 6-bromo-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one

A solution of 1-amino-4-bromo-1H-pyrrole-2-carboxylic acid methyl ester(2.9 g, 13.2 mmol) in formamide (12 mL) was heated at 180° C. for 5 hrs.The mixture was diluted with ethyl acetate (300 mL), and then washedwith water (100 mL*2), brine (100 mL*3). The organic layer was driedover sodium sulfate, filtered and concentrated under reduced pressure.The resulting solid was washed with PE/EA (4:1, 50 mL) to give6-bromo-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (1.4 g, yield 50%) asyellow solid. MS (ES+) requires: 213, 215. found 214, 216 [M+H]⁺;purity: 92%.

Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one

A mixture of 6-bromo-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (2.15 g, 10mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(4.2 g, 20 mmol), Cs₂CO₃ (9.8 g, 30 mmol), PdCl₂dppf (814 mg, 1 mmol),water (15 mL), ethanol (15 mL) and dioxane (70 mL) in a 250 mL flask wasdegassed with N₂ for 10 min, and then heated at 120° C. under N₂atmosphere overnight. The mixture was cooled to RT, followed by theaddition of silica gel (˜50 g). The residue was subjected to a silicagel column and eluted with DCM:MeOH (20:0-20:1) to afford6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (600mg, 28% yield) as a yellow solid. MS (ES+) requires: 215. found 216.1[M+H]⁺; purity: 90%.

Synthesis of4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazine

6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (600mg, 2.8 mmol) was treated with phosphorus oxychloride (20 mL) underreflux for 3 hours. The mixture was cooled to RT, concentrated underreduced pressure and the residue was diluted with ice water (100 mL).The mixture was extracted with dichloromethane (50 mL*4), and thecombined organic layers were dried by MgSO₄, filtered, concentrated togive 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazine(600 mg, 92% yield) as a brown solid. MS (ES+) requires: 233, 235. found234, 236 [M+H]⁺; purity: 90%.

Synthesis of tert-butyl3-(4-methylbenzylcarbamoyl)azetidine-1-carboxylate

A mixture of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (400 mg,1.99 mmol), p-tolylmethanamine (340 mg, 1.99 mmol), HBTU (907 mg, 2.39mmol) and diisopropylethylamine (1.03 g, 7.96 mmol) inN,N-dimethylformamide (10 mL) was stirred at RT overnight. LCMS and TLCindicated completion of the reaction. After quenched with water (50 mL),the reaction mixture was extracted with ethyl acetate (3×50 mL). Theorganic layers were separated, combined, washed with water (50 mL×2) andbrine (50 mL×3), dried over sodium sulfate, filtered and concentrated.The crude residue was purified by silica gel chromatography (petroleumether:ethyl acetate=4:1) to afford the title compound as a colorless oil(450 mg, yield: 74%). MS (ES+) C₁₇H₂₄N₂O₃ requires: 304. found: 249[M+H-56]⁺.

Synthesis of N-(4-methylbenzyl)azetidine-3-carboxamide

A mixture of tert-butyl3-(4-methylbenzylcarbamoyl)azetidine-1-carboxylate (400 mg, 1.32 mmol)in HCl/dioxane (10 mL) was stirred at RT overnight. The reaction mixturewas concentrated under reduced pressure to afford the title compound(250 mg, crude) as a yellow solid, which was directly used into the nextstep without further purification. MS (ES+) C₁₂H₁₆N₂O requires: 204.found: 205 [M+H]⁺.

Synthesis of1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(4-methylbenzyl)azetidine-3-carboxamide

A mixture of N-(4-cyanophenyl)azetidine-3-carboxamide (86 mg, 0.43mmol),4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazine (100mg, 0.43 mmol) and diisopropylethylamine (211 mg, 1.72 mmol) in dioxane(5 mL) was stirred at RT overnight. LCMS and TLC indicated completion ofthe reaction. The reaction mixture was concentrated under reducedpressure to afford a residue, which was purified by Prep-HPLC to givethe title compound (18.4 mg, 11%) as a white solid. MS (ES+) C₂₂H₂₃N₇Orequires: 401. found: 402 [M+H]⁺.

Synthesis of(S)—N-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)methyl)-1-p-tolylethanamine(Compound 10)

Synthesis of(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)methanol

To a solution of4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazine (1.0g, 4.3 mmol) and azetidin-3-ylmethanol (370 mg, 4.3 mmol) in a mixedsolvent of dichloromethane (20 mL) and isopropanol (5 mL) was addeddiisopropylethylamine (1.7 g, 12.9 mmol) at RT. After that, theresultant solution was stirred at RT overnight. The formed precipitatewas collected via filtration to give the title compound (1.0 g, 84%) asa gray solid. MS (ES+) C₁₄H₁₆N₆O requires: 284. found: 285 [M+H]⁺.

Synthesis of(S)—N-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)methyl)-1-p-tolylethanamine

A solution of(1-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidin-3-yl)methanol(200 mg, 0.7 mmol) and Dess-Martin reagent (597 mg, 1.4 mmol) inanhydrous N,N-dimethylformamide (5 mL) was stirred at RT for 2 hours.After that, to this mixture was added (S)-1-p-tolylethanamine (149 mg,1.1 mmol), acetic acid (0.5 mL), dichloromethane (5 mL) and methanol (5mL) at RT. The resultant mixture was stirred at RT for 5 mins, followedby the addition of sodium cyanoborohydride (88 mg, 1.4 mmol), and themixture was stirred at RT for overnight. The mixture was concentratedunder reduced pressure, and the residue was purified by Prep-HPLC toafford the title compound (50 mg, 18%) as a white solid. MS (ES+)C₂₃H₂₇N₇ requires: 401. found: 402 [M+H]⁺.

Synthetic Protocol 2

Synthetic Protocol 2 is shown above. Pyrrolotriazine (1) can besubstituted with azetidines (2 or 6) under nucleophilic aromaticsubstitution reaction conditions using an amine base such asdiisopropylethylamine (DIPEA) or triethylamine (TEA) in a polar solventsuch as dioxane to provide the piperazine-substituted pyrrolotriazine (3or 7). Pyrrolotriazine (3) can also be achieved via an amide bondcoupling reaction with amine (8). Azetidine (2) can be synthesized byreaction of A via an amide bond coupling to generate intermediate Bfollowed by deprotection. Pyrrolotriazine (3 or 7) can be coupled (LGtypically Cl, Br, I) to a boron, tin or zinc aryl, heteroaryl, alkenyl,alkyl reagent (2) via a palladium-mediated coupling reaction, e.g.,Suzuki, Stille, Negishi coupling, to provide the pyrrolotriazine (5 or9). Pyrrolotriazine (5) can also be achieved via an amide bond couplingreaction with amine (8).

As shown below, Compounds 42, 173, 184, and 221 were prepared usingsynthetic protocol 2.

Synthesis of1-(6-(1-(cyclopropanecarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-N-(4-methylbenzyl)azetidine-3-carboxamide(Compound 173)

Synthesis of 6-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine

A solution of 6-bromopyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (15.0 g,46.9 mmol) in POCl₃ (150 mL) was heated to 130° C. for 3 hrs. Thesolvent was evaporated. The residue was cooled to 0° C. and dissolvedwith 20% aq. NaHCO₃ (200 mL), extracted with EtOAc (200 mL*3). Theorganic layer was dried over Na₂SO₄ and concentrated to give6-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine (13 g, yield: 79.8%) as abrown solid.

Synthesis of methyl1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidine-3-carboxylate

A mixture of 6-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine (5.0 g, 21.7mmol), methyl azetidine-3-carboxylate hydrochloride (3.29 g, 21.7 mmol)and DIPEA (14.0 g, 109 mmol) in DCM (50 mL) was stirred at 26° C. for 16hrs. The mixture was washed with brine (25 mL). The organic layer wasdried over Na₂SO₄ and concentrated to give the desired product methyl1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidine-3-carboxylate (5.0g, yield: 74.2%). ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 7.88 (s, 1H), 7.84 (s,1H), 6.84 (s, 1H), 4.73-4.24 (m, 4H), 3.76-3.70 (m, 1H), 3.68 (s, 3H).

Synthesis of1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidine-3-carboxylic acid

A mixture of methyl1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidine-3-carboxylate (4.0g, 12.9 mmol) and NaOH (1.03 g, 25.8 mmol) in MeOH—H₂O (50 mL, 4:1) wasstirred at 26° C. for 16 hrs. The solvent was concentrated to removeMeOH. The residue was adjusted pH to 5 with 4N aq. HCl. The solid wasfiltered and dried in vacuo to give the desired product1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidine-3-carboxylic acid(3.5 g, yield: 91.6%). ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 7.89 (s, 1H),7.85 (s, 1H), 6.87 (s, 1H), 4.72-4.58 (m, 2H), 4.36-4.03 (m, 2H),3.65-3.61 (m, 1H).

Synthesis of1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-N-(4-methylbenzyl)azetidine-3-carboxamide

To the mixture of1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidine-3-carboxylic acid(3.5 g, 11.8 mmol) and Et₃N (5.97 g, 59.1 mmol) in DCM (50 mL) was addedHATU (5.38 g, 14.2 mmol) at 25° C. After being stirred for 15 mins,p-tolylmethanamine (1.43 g, 11.8 mmol) was added to the reaction at 25°C. The reaction mixture was stirred at 25° C. for 16 hrs. After LCMSshowed the reaction was complete, the reaction was diluted with DCM andwashed with brine. The organic layer was dried over Na₂SO₄ andconcentrated to give the title compound (3.0 g, yield: 63.6%) as a whitesolid.

Synthesis of tert-butyl4-(4-(3-((4-methylbenzyl)carbamoyl)azetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate

To a mixture of1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-N-(4-methylbenzyl)azetidine-3-carboxamide(400 mg, 1 mmol) in DME/H₂O (12 mL, 5:1) was added the boronic ester(450 mg, 1.5 mmol), Na₂CO₃ (348 mg, 3 mmol) and Pd(dppf)Cl₂ (37 mg, 0.05mmol) at 25° C. under N₂. The mixture was heated to 80° C. for 12 hrs.The mixture was filtered and concentrated to afford crude tert-butyl4-(4-(3-((4-methylbenzyl)carbamoyl)azetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate(300 mg) as a brown oil. This material was used without furtherpurification.

Synthesis ofN-(4-methylbenzyl)-1-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidine-3-carboxamide

To a solution of tert-butyl4-(4-(3-((4-methylbenzyl)carbamoyl)azetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate(300 mg, 0.6 mmol) in EtOAc (10 mL) was added HCl/EtOAc (10 mL, 4 M) at25° C. The reaction was stirred at 25° C. for 4 hrs. The solid wasfiltered and dried in vacuo to give crudeN-(4-methylbenzyl)-1-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidine-3-carboxamide(100 mg, yield: 41.7%) as a brown solid.

Synthesis of1-(6-(1-(cyclopropanecarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-N-(4-methylbenzyl)azetidine-3-carboxamide(Compound 173)

To a mixture ofN-(4-methylbenzyl)-1-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidine-3-carboxamide(100 mg, 0.248 mmol, crude) and Et₃N (75 mg, 0.744 mmol) in DCM (20 mL)was added cyclopropanecarbonyl chloride (26 mg, 0.248 mmol) at 0° C. Thereaction mixture was stirred at 25° C. for 2 hrs. After LCMS showed thereaction was complete, the reaction mixture was concentrated. Theresidue was purified by prep-HPLC to give the title compound (25 mg,yield: 21.2%) as a white solid. MS Calcd.: 470.6, MS Found: 471.3([M+1]⁺).

Synthesis of1-(6-(4-(2-hydroxy-2-methylpropoxy)phenyl)pyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(4-methylbenzyl)azetidine-3-carboxamide(Compound 221)

A mixture of(1-(6-(4-hydroxyphenyl)pyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(4-methylbenzyl)azetidine-3-carboxamide(50 mg, 0.12 mmol), 2,2-dimethyloxirane (345 mg, 4.8 mmol), sodiumiodide (72 mg, 0.48 mmol) and potassium carbonate (33 mg, 0.24 mmol) inN,N-dimethylformamide (0.5 mL) was stirred at 110° C. overnight. Thereaction mixture was cooled to RT and concentrated. The residue waspurified by Prep-HPLC to give the title compound: (2.3 mg, 4%) as awhite solid. MS (ES+) C₂₆H₃₀N₈O₂ requires: 485. found: 486 [M+H]⁺.

Synthesis of1-(6-(4-fluoro-3-(2-hydroxypropan-2-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-N-(4-methylbenzyl)azetidine-3-carboxamide(Compound 184)

To a solution of1-(6-(3-acetyl-4-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-N-(4-methylbenzyl)azetidine-3-carboxamide(80 mg, 0.175 mmol) in THF (3.00 mL) was added MeMgBr (0.26 mL, 0.53mmol, 2 M) dropwise at 0° C., then the solution was stirred at 25° C.for 2 hrs under N₂ atmosphere, after the starting material was consumedcompletely which was detected by LCMS, the reaction was quenched withsaturated NH₄Cl (5 mL), and extracted with EtOAc (5 mL*3), the combinedorganic layers were dried over Na₂SO₄, concentrated in vacuum andpurified by prep-HPLC to get the title compound (2.6 mg, yield: 3.14%).

Synthesis of(E)-N-(4-methylbenzyl)-1-(6-(2-(pyridin-2-yl)vinyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)azetidine-3-carboxamide(Compound 42)

To a mixture of1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-N-(4-methylbenzyl)azetidine-3-carboxamide(100 mg, 0.250 mmol), 2-vinylpyridine (31.6 mg, 0.300 mmol) and Et₃N (80mg, 0.750 mmol) in CH₃CN (10 mL) was added Pd₂(dba)₃ (11.4 mg, 0.013mmol) and (o-MeC₆H₄)₃P (7.6 mg, 0.025 mmol) at 20° C. under N₂. Thereaction mixture was stirred at 90° C. for 16 hrs under N₂. The reactionwas complete detected by LCMS. The mixture was filtered and the filtratewas concentrated. The crude product was purified by prep-HPLC to givethe title compound (15 mg, yield: 14.1%) as a white solid.

Synthetic Protocol 3

Synthetic Protocol 3 is shown above. Pyrrolotriazine (1) can besubstituted with azetidines (2 or 6) under nucleophilic aromaticsubstitution reaction conditions using an amine base such asdiisopropylethylamine (DIPEA) or triethylamine (TEA) in a polar solventsuch as dioxane to provide the piperazine-substituted pyrrolotriazine (3or 7). The leaving group of 3 or 7 can be replaced with aboron-containing group to give 5 or 11. Pyrrolotriazine (5) can also beachieved via an amide bond coupling reaction with amine (8). Azetidine(2) can be synthesized by reaction of A via an amide bond coupling togenerate intermediate B followed by deprotection. Pyrrolotriazine (5 or11) can be coupled (LG typically Cl, Br, I) to an aryl, heteroaryl,alkenyl, alkyl reagent (9) via a palladium-mediated coupling reaction toprovide pyrrolotriazine (10).

As shown below, Compounds 148 and 149 were prepared using syntheticprotocol 3.

Synthesis of(S)-1-(6-(3-amino-1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(1-(4-chlorophenyl)propyl)azetidine-3-carboxamideand(S)-1-(6-(5-amino-1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(1-(4-chlorophenyl)propyl)azetidine-3-carboxamide(Compound 148)

Synthesis of(S)-1-(6-bromopyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(1-(4-chlorophenyl)propyl)azetidine-3-carboxamide

A mixture of1-(6-bromopyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidine-3-carboxylic acid(950 mg, 3.2 mmol), (S)-1-(4-chlorophenyl)propan-1-amine (718 mg, 3.5mmol) and HATU (1.44 g, 3.8 mmol) and diisopropylethylamine (490 mg, 3.8mmol) in N,N-dimethylformamide (20 mL) was stirred at RT overnight. Thereaction was quenched with water (100 mL), filtered to afford the titlecompound (1 g, 70%) as a white solid. MS (ES+) C₁₉H₁₉BrClN₅O requires:447. found: 448 [M+H]⁺.

Synthesis of(S)—N-(1-(4-chlorophenyl)propyl)-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidine-3-carboxamide

A mixture of(S)-1-(6-bromopyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(1-(4-chlorophenyl)propyl)azetidine-3-carboxamide(500 mg, 1.1 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (425 mg, 1.7mmol), Pd(dppf)Cl₂ (164 mg, 0.2 mmol), dppf (150 mg) and potassiumacetate (220 mg, 2.2 mmol) in dioxane (15 mL) was degassed with N₂ forthree times and then heated at 80° C. overnight. The reaction mixturewas cooled to RT and directly concentrated. The residue was purified bysilica gel column (dichloromethane:methanol=50:1) to the title compound(300 mg, 54%) as a white solid. MS (ES+) C₂₅H₃₁BClN₅O₃ requires: 495.found: 496 [M+H]⁺.

Synthesis of(S)-1-(6-(3-amino-1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(1-(4-chlorophenyl)propyl)azetidine-3-carboxamide(Compound 148)

A mixture of(S)—N-(1-(4-chlorophenyl)propyl)-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidine-3-carboxamide(100 mg, 0.57 mmol), 4-bromo-1-methyl-1H-pyrazol-3-amine (40 mg, 0.57mmol), Pd(t-Bu₃P)Cl₂ (9 mg, 0.025 mmol) and cesium carbonate (73 mg,0.57 mmol) in THF/H₂O (4:1, 10 mL) was degassed with nitrogen for threetimes and heated at 80° C. for 3 hrs. The reaction mixture was cooled toRT and concentrated. The residue was purified by Prep-HPLC to give thetitle compound (24.3 mg, 9%) as a white solid. MS (ES+) C₂₃H₂₅ClN₈Orequires: 464. found: 465 [M+H]⁺.

Synthesis of(S)-1-(6-(5-amino-1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-yl)-N-(1-(4-chlorophenyl)propyl)azetidine-3-carboxamide(Compound 149)

A mixture of(S)—N-(1-(4-chlorophenyl)propyl)-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-f][1,2,4]triazin-4-yl)azetidine-3-carboxamide(100 mg, 0.57 mmol), 4-bromo-1-methyl-1H-pyrazol-5-amine (40 mg, 0.57mmol), Pd(t-Bu₃P)Cl₂ (9 mg, 0.025 mmol) and cesium carbonate (73 mg,0.57 mmol) in THF/H₂O (4:1, 10 mL) was degassed with nitrogen for threetimes and was heated at 80° C. for 3 h. The reaction mixture was cooledto RT and concentrated. The residue was purified by Prep-HPLC to givethe title compound (30.5 mg, 12%) as a white solid. MS (ES+) C₂₃H₂₅ClN₈Orequires: 464. found: 465 [M+H]⁺.

Synthesis of Selected Intermediates

Synthesis of2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol

To the mixture of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.94 g, 10mmol) and 2,2-dimethyloxirane (1.08 g, 15 mmol) in DMF (17 mL) was addedCs₂CO₃ (6.52 g, 20 mmol) at 25° C. The reaction was heated at 120° C.for 0.5 hr in a microwave reactor. After the reaction was complete whichwas detected by LCMS, the mixture was filtered and the filtrate wasconcentrated. The crude product was purified by flash silica gelchromatography to give the title compound (1.82 g, yield: 68.4%) as awhite solid.

Synthesis of (S)-3-(4-iodo-1H-pyrazol-1-yl)-2-methylbutan-2-ol and(R)-3-(4-iodo-1H-pyrazol-1-yl)-2-methylbutan-2-ol

To a solution of 4-iodo-1H-pyrazole (1 g, 5.1 mmol) and2,2,3-trimethyloxirane (1.3 g, 15.4 mmol) in acetonitrile (5 mL) wasadded cesium carbonate (2.0 g, 6.2 mmol), and the resultant mixture washeated at 120° C. under microwave for 3 hrs. The reaction mixture wascooled to RT and directly concentrated. The residue was purified byPrep-HPLC to give the title compound (600 mg, 42%) as a white solid. MS(ES+) requires: 280. found: 281 [M+H]⁺. The above racemate was separatedby Chiral-HPLC to afford the desired enantiomers (peak 1, 250 mg, ee:100%), (peak 2, 250 mg, ee: 99%).

Synthesis of (2S,3R)-3-(4-iodo-1H-pyrazol-1-yl)butan-2-ol and(2R,3S)-3-(4-iodo-1H-pyrazol-1-yl)butan-2-ol

To a solution of 4-iodo-1H-pyrazole (1 g, 5.1 mmol) andtrans-2,3-dimethyloxirane (1.1 g, 15.6 mmol) in acetonitrile (3 mL) wasadded cesium carbonate (2.0 g, 6.2 mmol). The mixture was heated at 120°C. under microwave for 3 hrs. The reaction mixture was cooled to RT andconcentrated. The residue was purified by Prep-HPLC to give the titlecompound (600 mg, 43%) as a white solid. MS (ES+) C₇H₁₁IN₂O requires:266. found: 267 [M+H]⁺.

The above racemate was separated by Chiral-HPLC to afford the desiredenantiomer (peak 1, 250 mg, ee: 98%), (peak 2, 250 mg, ee: 99%).

Synthesis of (R)-1,1,1-trifluoro-3-(4-iodo-1H-pyrazol-1-yl)propan-2-oland (S)-1,1,1-trifluoro-3-(4-iodo-1H-pyrazol-1-yl)propan-2-ol

To a solution of 4-iodo-1H-pyrazole (1 g, 5.1 mmol) and2-(trifluoromethyl)oxirane (700 mg, 6.2 mmol) in a acetonitrile (5 mL)was added cesium carbonate (2.0 g, 6.2 mmol). The mixture was at 120° C.under microwave for 3 hrs. The reaction mixture was cooled to RT andconcentrated. The residue was purified by silica gel column(dichloromethane:methanol=70:1) to give the title compound (1.4 g, 88%)as a white solid. MS (ES+) C₆H₆F₃IN₂O requires: 306. found: 307 [M+H]⁺.

The above racemate (800 mg) was separated by Chiral-HPLC to afford thedesired enantiomers (peak 1, 280 mg, ee: 99%), (peak 2, 300 mg, ee:99%).

Synthesis of2-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butan-2-ol

Synthesis of 3-hydroxy-3-methylbutyl methanesulfonate

3-Methylbutane-1,3-diol (3.83 g, 36.8 mmol) was dissolved indichloromethane (150 ml), followed by the addition of triethylamine(6.66 mL) and methanesulfonyl chloride (3.13 mL) at 0° C. After stirringat RT for 7.5 hrs, the reaction was quenched by ethyl acetate and water,and the organic layer was dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure to obtain the titlecompound as a colorless oil (4.79 g, 72%).

Synthesis of2-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butan-2-ol

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(500 mg, 2.58 mmol), 3-hydroxy-3-methylbutyl methanesulfonate (938 mg,5.16 mmol) and cesium carbonate (1.68 g, 5.16 mmol) inN,N-dimethylformamide (10 mL) was heated at 80° C. overnight. LCMS andTLC indicated the completion of the reaction. The reaction mixture wascooled to RT and concentrated to give a residue, which was purified bysilica gel chromatography (petroleum ether: ethyl acetate=1:1) to affordthe title compound as a colorless oil (350 mg, 49%). MS (ES+)C₁₄H₂₅BN₂O₃ requires: 280. found: 281 [M+H]⁺.

Synthesis of (R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-dioxolane and(S)-4-(4-bromophenyl)-2,2-dimethyl-1,3-dioxolane

Synthesis of ethyl 2-(4-bromophenyl)-2-oxoacetate

To a stirred mixture of bromobenzene (0.7 mL, 6.5 mmol) and ethyl2-chloro-2-oxoacetate (0.7 mL, 6.5 mmol) in dichloromethane (12 mL) wasadded aluminum trichloride (1.7 g, 12.5 mmol) at 0° C. The reaction waswarmed to RT slowly and stirred at RT for 18 h. After poured into conc.hydrochloric acid at 0° C., the mixture was extracted withdichloromethane (3×100 mL). The combined organic layers were washed withbrine (100 mL), dried over anhydrous sodium sulfate and filtered andconcentrated under reduced pressure. The resultant oily matter waspurified by silica gel column chromatography (ethyl acetate:petroleumether=1:20) to afford the title compound (1.0 g, 60%) as a yellow oil.MS (ES+) C₁₀H₉BrO₃ requires: 256. found: 257, 259 [M+H]⁺.

Synthesis of 1-(4-bromophenyl)ethane-1,2-diol

To a solution of ethyl 2-(4-bromophenyl)-2-oxoacetate (1.0 g, 4.0 mmol)in ethanol (20 mL) was added sodium borohydride (380 mg, 10.0 mmol) at0° C., and the mixture was stirred at RT for 12 h. The reaction wasquenched with propan-2-one (10 mL) and concentrated under reducedpressure. The resultant was purified by silica gel column chromatography(dichloromethane:methanol=10:1) to afford the title compound (700 mg,81%) as a white solid. MS (ES+) C₈H₉BrO₂ requires: 216. found: 217, 219[M+H]⁺.

Synthesis of (R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-dioxolane and(S)-4-(4-bromophenyl)-2,2-dimethyl-1,3-dioxolane

To a solution of 1-(4-bromophenyl)ethane-1,2-diol (700 mg, 3.2 mmol) and2,2-dimethoxypropane (666 mg, 6.4 mmol) in propan-2-one (10 mL) wasadded 4-methylbenzenesulfonic acid (110 mg, 0.64 mmol), and the reactionmixture was stirred at RT overnight. The mixture was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate: petroleum ether=1:10) to afford the titlecompound (500 mg, 61%) as a light yellow oil. MS (ES+) C₁₁H₁₃BrO₂requires: 256. found: 257, 259 [M+H]⁺.

Then chiral-HPLC purification to afford Peak 1 (180 mg, 36%), Peak 2(150 mg, 30%).

Synthesis of2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol

Synthesis of 2-(4-bromophenyl)propan-2-ol

To the mixture of 1,4-dibromobenzene (5.2 g, 22.0 mmol) in THF (50 mL)was added dropwise n-BuLi (8.9 mL, 22.0 mmol, 2.5 M) at −60° C. Theresulting mixture was stirred at −60° C. for 1 hr, then a mixture ofacetone (3.8 g, 65.5 mmol) in THF (10 mL) was added dropwise at −60° C.After addition, the mixture was allowed to 20° C. slowly. After 1 hr,TLC (PE) showed the starting material was consumed completely. Thereaction was quenched by sat. NH₄Cl (50 mL). The mixture was extractedwith EtOAc (50 mL*3). The combined organic layers were dried over Na₂SO₄and filtered. After concentration, the residue was purified by MPLC togive the title compound (3.0 g, yield: 63.8%) as a yellow oil.

Synthesis of2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol

A mixture of 2-(4-bromophenyl)propan-2-ol (2.80 g, 13.0 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.30 g,13.0 mmol), AcOK (2.60 g, 26.0 mmol) and Pd(dppf)Cl₂ (476 mg, 0.65 mmol)in dioxane (60 mL) was stirred at 80° C. for 2 hrs under N₂. After HPLCand TLC (PE:EtOAc=3:1) showed the reaction was complete, the mixture wasconcentrated and purified by MPLC to give the title compound (2.00 g,yield: 58.8%) as a white solid.

Synthesis ofpyrrolidin-1-yl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone

Synthesis of (4-bromophenyl)(pyrrolidin-1-yl)methanone

To a stirred mixture of 4-bromobenzoic acid (2.00 g, 10.0 mol) and Et₃N(3.03 g, 30.0 mmol) in DCM (30 mL) was added HATU (4.18 g, 11.0 mmol) at30° C. After 15 mins, pyrrolidine (972 mg, 12.0 mmol) was added into themixture, which was stirred at 30° C. for 16 hrs. After LCMS and TLC(PE:EtOAc=2:1) showed the reaction was complete, the mixture wasconcentrated and purified by column chromatography on silica gel(PE:EtOAc=1:0-20:1-10:1-5:1-3:1) to give the title compound (2.20 g,yield: 86.9%) as a white solid.

Synthesis ofpyrrolidin-1-yl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone

A mixture of (4-bromophenyl)(pyrrolidin-1-yl)methanone (2.20 g, 8.70mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.43g, 9.57 mmol), AcOK (1.17 g, 17.4 mmol) and Pd(dppf)Cl₂ (110 mg) indioxane (20 mL) was stirred at 100° C. for 16 hrs under N₂. After LCMSand TLC (PE:EtOAc=2:1) showed the reaction was complete, the mixture wasconcentrated and purified by column chromatography on silica gel(PE:EtOAc=1:0˜50:1˜20:1˜10:1˜5:1˜3:1) to give the title compound (2.15g, yield: 83.4%) as a white solid.

Synthesis of (4-cyclopropylphenyl)boronic acid

To a mixture of 1-bromo-4-cyclopropylbenzene (4.00 g, 20.3 mmol) in THF(50 mL) was added dropwise n-BuLi (9.7 mL, 2.5 M, 24.4 mmol) at −78° C.After addition, the resulting mixture was stirred at −78° C. for 1 hr.Then (i-PrO)₃B (7.63 g, 40.6 mmol) was added at −78° C. After stirringfor 30 min, the resulting mixture was stirred at 20° C. for 16 hrs. TLC(PE) showed the reaction was complete. The reaction was quenched by 1 Mof aq. HCl (50 mL), the mixture was extracted with EtOAc (50 mL*3). Thecombined organics were dried over Na2SO4 and concentrated. The residuewas purified by column chromatography on silica gel (PE:EtOAc=20/1 to3/1) to give the title compound (800 mg, yield:24.3%) as a white solid.

Synthesis of 4-bromo-1-(tert-butoxy)-2-fluorobenzene

To a mixture of 4-bromo-2-fluorophenol (19.1 g, 0.1 mol) and Mg(ClO₄)₂(2.23 g, 0.01 mol) in DCM (50 mL) was added Boc₂O (43.6 g, 0.2 mol) at25° C. The reaction was heated at 40° C. for 1 hr. Then 1 eq. of Boc₂O(21.8 g, 0.1 mol) was added to the reaction. The reaction was heated at40° C. for 12 hrs. The solution was concentrated and purified by silicagel chromatography (PE) to give the title compound (15.0 g, yield:60.7%) as a colorless oil.

Synthesis of 1-bromo-4-(tert-pentyloxy)benzene

To a mixture of Ni(acac)₂ (150 mg, 0.58 mmol) in toluene (50 mL) washeated at 120° C. for 8 hrs. Then 4-bromophenol (1.73 g, 10 mmol) and2-bromo-2-methylbutane (4.50 g, 30 mmol), NaHCO₃ (1.68 g, 20 mmol) wasadded to the reaction mixture. The reaction was heated at 60° C. for 16hrs. The starting materials wasn't consumed, but a new point wasdetected by TLC. The mixture was extracted with EtOAc (30 mL), washedwith aq. NaOH (20 mL) and brine (20 mL). The organic layer was driedover Na₂SO₄ and concentrated. The residue was purified by prep-TLC (PE)to give the title compound (150 mg, yield: 6.17%) as a colorless oil.

Synthesis of 1-(tert-butoxycarbonyl)-3-hydroxyazetidine-3-carboxylicacid

Synthesis of tert-butyl3-cyano-3-((trimethylsilyl)oxy)azetidine-1-carboxylate

tert-butyl 3-oxoazetidine-1-carboxylate (500 mg, 2.9 mmole) wasdissolved in 5 mL DCM and triethylamine (0.41 mL, 2.9 mmole) was addedfollowed by TMS-cyanide (1.1 mL, 8.8 mmole) and the reaction mixture wasstirred at room temperature overnight. The reaction mixture was dilutedwith DCM and washed with saturated sodium bicarbonate solution. Theorganic layer was dried over sodium sulfate and filtered and evaporatedto give tert-butyl3-cyano-3-((trimethylsilyl)oxy)azetidine-1-carboxylate in crude formwhich was used directly in the next step without further purification.

Synthesis of 1-(tert-butoxycarbonyl)-3-hydroxyazetidine-3-carboxylicacid

tert-butyl 3-cyano-3-((trimethylsilyl)oxy)azetidine-1-carboxylate (0.79g, 2.9 mmole) was dissolved in a mixture of acetic acid (4.4 mL) andconcentrated hydrochloric acid (3.4 mL) and heated to 100° C. for 2hours. The solvent was evaporated exhaustively and then co-evaporated(x3) with toluene. The resulting residue was triturated withether/hexane and filtered to give the desired product in crude form as ayellow semisolid. This material was suspended in 10 mL DCM anddiisopropylamine (1.1 mL, 6.4 mmole) was added followed by di-tert-butyldicarbonate (956 mg, 4.4 mmole) was added and stirred at roomtemperature overnight. The reaction mixture was diluted with DCM andpartition with water. The aqueous layer was brought to pH ˜3 with 1M HCland then extracted 4 times with DCM. The combined organics were driedover sodium sulfate and filtered and evaporated to give 320 mg (50%) of1-(tert-butoxycarbonyl)-3-hydroxyazetidine-3-carboxylic acid as a whitesolid.

Synthesis of tert-butyl3-(N-(4-methylbenzyl)sulfamoyl)azetidine-1-carboxylate

tert-butyl 3-(chlorosulfonyl)azetidine-1-carboxylate (40 mg, 0.16 mmole)dissolved in 0.5 mL pyridine and 4-methylbenzylamine (24 uL, 0.19 mmole)added and stirred at room temperature overnight. Solvent evaporatedexhaustively and then triturated the resulting residue with water. Theresulting suspension filtered and washed with water and suction dried togive 25 mg (47%) of tert-butyl3-(N-(4-methylbenzyl)sulfamoyl)azetidine-1-carboxylate as a pale yellowsolid.

Synthesis of 4-cyclopropylbenzaldehyde

To a mixture of 4-bromobenzaldehyde (13.5 g, 0.0734 mol),cyclopropylboronic acid (6.3 g, 0.0734 mol), K₃PO₄.3H₂O (33.3 g, 0.147mol) and PCy₃ (20.5 g, 0.0734 mol) in toluene/H₂O (180 mL, 5:1) wasadded Pd(OAc)₂ (500 mg) under N₂. The reaction was heated at 80° C. for15 hrs under N₂. The reaction was complete detected by LCMS. Toluene andH₂O were removed by vacuum. The crude product was purified by columnchromatography on silica gel (eluted with PE:EtOAc=20:1) to give thetitle compound (5.0 g, yield: 93.2%) as a yellow oil. ¹H-NMR (400 MHz,CDCl₃) δ ppm 9.94 (s, 1H), 7.76 (d, 2H, J=7.6 Hz), 7.18 (d, 2H, J=7.6Hz), 2.00-1.94 (m, 1H), 1.11-1.07 (m, 2H), 0.82-0.80 (m, 2H).

Synthesis of(S,E)-N-(4-cyclopropylbenzylidene)-2-methylpropane-2-sulfinamide

To a mixture of 4-cyclopropylbenzaldehyde (5.0 g, 0.0685 mol) and CuSO₄(21.9 g, 0.137 mol) in dry DCM (200 mL) was added(S)-2-methylpropane-2-sulfinamide (16.6 g, 0.137 mol). The reactionmixture was stirred at 40° C. for 24 hrs. The reaction was completedetected by LCMS. The mixture was filtered and the filtrate wasconcentrated to give crude product. PE was added to the mixture, and themixture was cooled to −78° C., filtered and the filtrate wasconcentrated to give crude product. EtOAc (150 mL) was added themixture, and then the mixture was washed by H₂O (200 mL*2), brine (150mL*2), then the organics was dried by vacuum to give product (6 g,yield: 70.3%) as a yellow oil.

Synthesis of(S)—N—((S)-1-(4-cyclopropylphenyl)propyl)-2-methylpropane-2-sulfinamide

To a mixture of(S,E)-N-(4-cyclopropylbenzylidene)-2-methylpropane-2-sulfinamide (1.0 g,4.02 mmol) in THF (20 mL) cooled to −78° C. was added ethyllithium(0.290 mg, 8.03 mmol) dropwise under N₂. The reaction mixture wasstirred at 29° C. for 15 hrs under N₂. The reaction was completedetected by LCMS. The reaction was quenched with aq. NH₄Cl (10 mL) andextracted with 50 mL of EtOAc carefully. The organic layer was separatedand concentrated to give crude product. The crude product was purifiedby column chromatography on silica gel (eluted with PE:EtOAc=20:1) togive product (1.05 g, yield: 93.8%) as a yellow oil.

Synthesis of (S)-1-(4-cyclopropylphenyl)propan-1-amine

A mixture of(S)—N—((S)-1-(4-cyclopropylphenyl)propyl)-2-methylpropane-2-sulfinamide(1.05 g, 3.76 mmol) in HCl/EtOAc (4 M, 50 mL) was stirred at 25° C. for5 hrs. The reaction was complete detected by TLC (PE:EtOAc=1:2,R_(f)=0). The reaction mixture was filtered and the filter cake waswashed with EtOAc (5 mL), dried in vacuum to give the title compound(0.64 g, yield: 97.1%) as a white solid.

Synthesis of methyl 2-(2,4-dichlorophenyl)acetate

2-(2,4-Dichlorophenyl)acetic acid (1.0 g, 4.9 mmol) in MeOH (20 mL)saturated with HCl gas was stirred at 60° C. for 1 hr. After thestarting material was consumed completely detected by TLC, the solutionwas concentrated in vacuum to get the title compound (0.9 g, 84.1%) asyellow oil.

Synthesis of methyl 2-(2,4-dichlorophenyl)propanoate

To the mixture of methyl 2-(2,4-dichlorophenyl)acetate (0.5 g, 2.29mmol) in THF (10 mL) was added NaH (0.12 g, 2.98 mmol) at 0° C.portionwise, then the mixture was stirred at 25° C. for 0.5 hr, then tothe mixture was added MeI (0.42 g, 2.98 mmol) dropwise, the mixture wasstirred at 25° C. for 2 hrs. After the starting material was consumedcompletely detected by TLC, the mixture was quenched by H₂O (10 mL),extracted with EtOAc (10 mL*3). The organics were dried over Na₂SO₄ andconcentrated in vacuum to get the title compound (0.3 g, yield: 50.8%)as yellow oil.

Synthesis of 2-(2,4-dichlorophenyl)propanoic acid

To the mixture of methyl 2-(2,4-dichlorophenyl)propanoate (0.5 g, 2.15mmol) in MeOH (10 mL) and H₂O (5 mL) was added NaOH (0.17 g, 4.30 mmol),then the mixture was stirred at 25° C. for 3 hrs. After the startingmaterial was consumed completely detected by TLC, the organic solventwas evaporated in vacuum and the aqueous phase was acidified withdiluted aq. HCl to pH=5, the aqueous phase was extracted with EtOAc (10mL*4), the organic layers were dried over Na₂SO₄ and concentrated to getthe title compound (0.3 g, yield: 63.8%) as yellow oil.

Synthesis of 2-(2,4-dichlorophenyl)-2-hydroxyacetic acid

To the mixture of 2,4-dichlorobenzaldehyde (1.0 g, 5.75 mmol) in CH₃CN(30 mL) was added TMSCN (0.68 g, 6.90 mmol), DMAP (50 mg), then themixture was stirred at 25° C. for 8 hrs, then the mixture wasconcentrated in vacuum and dissolved in HCl (30 mL, 6 M), the mixturewas stirred at 70° C. for 4 hrs, then the solution was concentrated invacuum to get the title compound as crude product (0.4 g).

Indications

The compounds described herein can be useful for treating conditionsassociated with aberrant Kit activity. Activating mutations in Kit arefound in multiple indications, including systemic mastocytosis, GIST(gastrointestinal stromal tumors), AML (acute myeloid leukemia),melanoma, and seminoma.

Mastocytosis refers to a group of disorders characterized by excessivemast cell accumulation in one tissue, or in multiple tissues.Mastocytosis is subdivided into two groups of disorders: (1) cutaneousmastocytosis (CM) describes forms that are limited to the skin; and (2)systemic mastocytosis (SM) describes forms in which mast cellsinfiltrate extracutaneous organs, with or without skin involvement. SMis further subdivided into four forms: indolent (ISM), smoldering (SSM),aggressive (ASM), SM with associated hemotologic non-mast cell lineagedisease (SM-AHNMD), and mast cell leukemia (MCL).

Diagnosis of systemic mastocytosis is based on histological andcytological study of bone marrow showing infiltration by mast cells offrequently atypical morphology, which frequently abnormally expressnon-mast cell markers (CD25 and/or CD2). An elevated level of serumtryptase above 20 ng/mL or the presence of an activating mutation of Kitcan confirm the diagnosis.

Activating mutations at the D816 position are found in the vast majorityof mastocytosis cases, with the most common mutations being D816V andD816H, and D816Y. The D816V mutation is found in the activation loop ofthe kinase domain, and leads to constitutive activation.

The compounds described herein may also be useful to treat GIST.Complete surgical resection remains the principal treatment of choicefor patients with a primary GIST. Surgery is effective in approximately50% of patients with GIST. Of the remaining patients, tumor recurrenceis frequent. Primary treatment with a Kit inhibitor such as imatinib hasalso been shown to be sufficient for initial treatment. However,resistance to imatinib occurs within months through somatic mutation.These secondary imatinib resistant mutations are most frequently locatedon exon 11, 13, 14, 17 or 18. Sunitinib is the standard of care secondline treatment for most imatinib resistant tumors and is effective forthose containing mutations in exons 11, 13 and 14. However, secondarykit mutations in exons 17 and 18 are resistant to sunitinib treatmentand furthermore, tumors containing tertiary resistance mutations in exon17 and 18 emerge several months after sunitinib treatment. Regorafenibhas shown promising results in a phase 3 clinical trial of imatinib,sunitinib resistant GISTs with activity against several exon 17 and 18mutations, with the exception of the D816 mutant which remainsrefractory to all treatments. Regorafenib has been approved for 3rd lineGIST treatment.

The compounds described herein may also be useful in treating AML. SomeAML patients harbor Kit mutations as well, with the majority of thesemutations at the D816 position.

In addition, mutations in Kit have been linked to Ewing's sarcoma, DLBCL(diffuse large B cell lymphoma), dysgerminoma, MDS (myelodysplasticsyndrome), NKTCL (nasal NK/T-cell lymphoma), and CMML (chronicmyelomonocytic leukemia).

Pharmaceutical Compositions

While it is possible for a compound disclosed herein to be administeredalone, it is preferable to administer the compound as a pharmaceuticalformulation, where the compound is combined with one or morepharmaceutically acceptable excipients or carriers. The compoundsdisclosed herein may be formulated for administration in any convenientway for use in human or veterinary medicine. In certain embodiments, thecompound included in the pharmaceutical preparation may be activeitself, or may be a prodrug, e.g., capable of being converted to anactive compound in a physiological setting.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

Examples of pharmaceutically acceptable carriers include: (1) sugars,such as lactose, glucose and sucrose; (2) starches, such as corn starchand potato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21)cyclodextrins such as Captisol®; and (22) other non-toxic compatiblesubstances employed in pharmaceutical formulations.

Examples of pharmaceutically acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders,granules and the like) can include one or more pharmaceuticallyacceptable carriers, such as sodium citrate or dicalcium phosphate,and/or any of the following: (1) fillers or extenders, such as starches,lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders,such as, for example, carboxymethylcellulose, alginates, gelatin,polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such asglycerol; (4) disintegrating agents, such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate; (5) solution retarding agents, such as paraffin;(6) absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, cetyl alcohol and glycerolmonostearate; (8) absorbents, such as kaolin and bentonite clay; (9)lubricants, such a talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and(10) coloring agents.

Liquid dosage forms can include pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the active ingredient, the liquid dosage forms may contain inertdiluents commonly used in the art, such as, for example, water or othersolvents, solubilizing agents and emulsifiers, such as ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (inparticular, cottonseed, groundnut, corn, germ, olive, castor and sesameoils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Ointments, pastes, creams and gels may contain, in addition to an activecompound, excipients, such as animal and vegetable fats, oils, waxes,paraffins, starch, tragacanth, cellulose derivatives, polyethyleneglycols, silicones, bentonites, silicic acid, talc and zinc oxide, ormixtures thereof.

Powders and sprays can contain, in addition to an active compound,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays can additionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any methods well known in the art of pharmacy. Theamount of active ingredient which can be combined with a carriermaterial to produce a single dosage form will vary depending upon thehost being treated, the particular mode of administration. The amount ofactive ingredient that can be combined with a carrier material toproduce a single dosage form will generally be that amount of thecompound which produces a therapeutic effect.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically acceptablecarrier, and with any preservatives, buffers, or propellants that may berequired.

When the compounds disclosed herein are administered as pharmaceuticals,to humans and animals, they can be given per se or as a pharmaceuticalcomposition containing, for example, 0.1 to 99.5% (more preferably, 0.5to 90%) of active ingredient in combination with a pharmaceuticallyacceptable carrier.

The formulations can be administered topically, orally, transdermally,rectally, vaginally, parentally, intranasally, intrapulmonary,intraocularly, intravenously, intramuscularly, intraarterially,intrathecally, intracapsularly, intradermally, intraperitoneally,subcutaneously, subcuticularly, or by inhalation.

Dosages

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient that is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound disclosed hereinemployed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the duration of the treatment, otherdrugs, compounds and/or materials used in combination with theparticular compound employed, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound that is the lowest dose effective to producea therapeutic effect. Such an effective dose will generally depend uponthe factors described above. Generally, intravenous,intracerebroventricular and subcutaneous doses of the compounds of thisinvention for a patient will range from about 0.0001 to about 100 mg perkilogram of body weight per day. If desired, the effective daily dose ofthe active compound may be administered as two, three, four, five, sixor more sub-doses administered separately at appropriate intervalsthroughout the day, optionally, in unit dosage forms. In someembodiments, the dose will be 1-20, or 5-10 mg per kilogram of bodyweight, administed twice daily.

Examples

The following examples are intended to be illustrative, and are notmeant in any way to be limiting.

NMR and LC MS data for compounds disclosed herein are shown below.

Compound Synthetic LC/MS Number Method ¹H MR M + 1 1 1 ¹H NMR (400 MHz,DMSO-d₆) δ 8.67 (t, J = 5.9 Hz, 1H), 388 8.01 (s, 1H), 7.92 (t, J = 1.2Hz, 1H), 7.85-7.72 (m, 2H), 7.40-7.20 (m, 5H), 6.89 (d, J = 0.9 Hz, 1H),4.79-4.53 (m, 3H), 4.45-4.15 (m, 4H), 3.84 (s, 3H), 3.70-3.59 (m, 1H) 21 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 12.81 (s, 1H), 8.61 388 (t, 1H, J =6.0 Hz), 8.07 (s, 1H), 7.94 (d, 1H, J = 1.2 Hz), 7.85 (s, 1H), 7.79 (s,1H), 7.16 (d, 2H, J = 8.0 Hz), 7.12 (d, 2H, J = 8.0 Hz), 6.90 (d, 1H, J= 1.2 Hz), 4.70-4.17 (m, 6H), 3.66-3.61 (m, 1H), 2.27 (s, 3H) 3 2 ¹H NMR(500 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.88 (d, J = 388 1.6 Hz, 1H), 7.76(d, J = 0.8 Hz, 1H), 7.76 (s, 1H), 7.23 (d, J = 7.7 Hz, 2H), 7.11 (d, J= 7.7 Hz, 2H), 6.82 (d, J = 1.7 Hz, 1H), 4.60 (s, 1H), 4.32-4.15 (m,2H), 3.84 (m, 4H), 3.68 (s, 2H), 2.92 (m, 1H), 2.75 (d, J = 7.1 Hz, 2H),2.27 (s, 3H). 4 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.66 (br.s, 1H), 3988.20 (s, 1H), 7.82 (s, 1H), 7.79 (d, 2H, J = 7.6 Hz), 7.40 (t, 2H, J =7.6 Hz), 7.24-7.20 (m, 1H), 7.17-7.12 (m, 5H), 4.27 (br.s, 2H), 2.27 (s,3H) 5 2 ¹H-NMR (500 MHz, CDCl₃) δ ppm 7.87 (s, 1H), 7.71 (d, 399 2H, J =8.5 Hz), 7.67-7.65 (m, 4H), 7.53 (s, 1H), 7.46-7.43 (m, 1H), 6.59 (s,1H), 4.68 (br, 4H), 3.94 (s, 3H), 3.72- 3.68 (m, 1H) 6 1 ¹H-NMR (500MHz, CDCl₃) δ ppm 7.84 (s, 1H), 7.66 (s, 402 1H), 7.63 (d, 1H, J = 1.0Hz), 7.53 (s, 1H), 7.19 (d, 2H, J = 8.5 Hz), 7.16 (d, 2H, J = 8.0 Hz),6.58 (s, 1H), 5.85 (br. s., 1H), 4.61 (br. s., 4H), 4.46 (d, 2H, J = 5.0Hz), 3.94 (s, 3H), 3.53-3.49 (m, 1H), 2.34 (s, 3H) 7 1 ¹H-NMR (500 MHz,DMSO-d₆) δ ppm 8.84 (d, 1H, J = 402 7.0 Hz), 8.02 (s, 1H), 7.93 (d, 1H,J = 1.5 Hz), 7.81(s, 1H), 7.80 (s, 1H), 7.16 (d, 2H, J = 7.0 Hz), 7.11(d, 2H, J = 7.5 Hz), 6.89 (d, 1H, J = 1.5 Hz), 4.85-4.10 (m, 5H), 3.84(s, 3H), 3.41 (s, 2H), 2.27 (s, 3H) 8 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm8.63 (t, 1H, J = 5.6 402 Hz), 8.07 (d, 1H, J = 1.2 Hz), 7.88 (s, 1H),7.40 (d, 1H, J = 2.0 Hz), 7.15 (d, 2H, J = 8.0 Hz), 7.12 (d, 2H, J = 8.4Hz), 6.94 (d, 1H, J = 1.2 Hz), 6.53 (d, 1H, J = 2.0 Hz), 4.80- 4.57 (m,2H), 4.42-4.14 (m, 4H), 3.95 (s, 3H), 3.66-3.55 (m, 1H), 2.26 (s, 3H) 92 ¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (t, J = 5.9 Hz, 1H), 402 7.83 (d, J =1.5 Hz, 1H), 7.79 (s, 1H), 7.57 (d, J = 1.3 Hz, 1H), 7.43 (d, J = 1.3Hz, 1H), 7.20-7.09 (m, 3H), 6.86 (d, J = 1.6 Hz, 1H), 4.64 (m, 2H), 4.27(m, 4H), 3.66 (m, 4H), 2.27 (s, 3H) 10 1 ¹H-NMR (400 MHz, CDCl₃) δ ppm7.81 (s, 1H), 7.67 (s, 402 1H), 7.60 (d, 1H, J = 1.6 Hz), 7.53 (s, 1H),7.22-7.14 (m, 4H), 6.54 (d, 1H, J = 1.6 Hz), 4.60 (br s, 1H), 4.34-4.19(m, 2H), 3.94-3.91 (m, 4H), 3.75 (q, 1H, J = 6.4 Hz), 2.87- 2.82 (m,2H), 2.75-2.70 (m, 1H), 2.33 (s, 3H), 1.36 (d, 3H, J = 6.8 Hz) 11 1¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.01 (s, 1H), 7.88 402 (d, 1H, J = 1.2Hz), 7.77 (s, 1H), 7.75 (s, 1H), 7.23 (d, 2H, J = 8.0 Hz), 7.11 (d, 2H,J = 8.0 Hz), 6.82 (s, 1H), 4.58 (br. s., 1H), 4.19 (br. s., 2H), 3.84(s, 3H), 3.79 (br. s., 1H), 3.70-3.62 (m, 1H), 2.92-2.81 (m, 1H),2.72-2.61 (m, 1H), 2.26 (br., s., 4 H), 1.24 (d, 3H, J = 6.4 Hz) 12 2 ¹HNMR (400 MHz, DMSO-d₆) δ 8.58 (t, J = 5.8 Hz, 1H), 404 7.88-7.73 (m,2H), 7.25-7.06 (m, 4H), 6.79 (d, J = 1.8 Hz, 1H), 6.24 (s, 1H),4.96-3.94 (m, 8H), 3.79 (t, J = 5.4 Hz, 2H), 3.60 (t, J = 8.1 Hz, 1H),2.40 (s, 2H), 2.26 (s, 3H) 13 2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.66 (t, J =5.9 Hz, 1H), 406 8.00 (s, 1H), 7.92 (d, J = 1.6 Hz, 1H), 7.82-7.73 (m,2H), 7.37-7.27 (m, 2H), 7.20-7.13 (m, 2H), 6.88 (d, J = 1.6 Hz, 1H),4.78-4.50 (m, 2H), 4.32 (d, J = 5.8 Hz, 4H), 3.84 (s, 3H) 14 1 ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 8.72 (t, 1H, J = 5.6 408 Hz), 8.01 (s, 1H),7.92 (d, 1H, J = 1.2 Hz), 7.80 (s, 1H), 7.79 (s, 1H), 6.89 (d, 1H, J =1.6 Hz), 6.76 (d, 1H, J = 3.2 Hz), 6.63 (dd, 1H, J = 1.2, 3.2 Hz),4.78-4.09 (m, 6H), 3.84 (s, 3H), 3.62-3.55 (m, 1H), 2.39 (s, 3H) 15 1¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.73 (t, 1H, J = 5.6 408 Hz), 8.01 (s,1H), 7.92 (d, 1H, J = 1.6 Hz), 7.80 (s, 1H), 7.79 (s, 1H), 6.96 (s, 1H),6.89 (d, 1H, J = 1.6 Hz), 6.81 (s, 1H), 4.69-4.60 (m, 2H), 4.43 (d, 2H,J = 6.0 Hz), 4.38- 4.19 (m, 2H), 3.84 (s, 3H), 3.63-3.56 (m, 1H), 2.16(s, 3H) 16 1 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 10.34 (s, 1H), 8.00 408 (s,1H), 7.93 (s, 1H), 7.81 (s, 1H), 7.78 (s, 1H), 7.66 (d, 2H, J = 8.8 Hz),7.39 (d, 2H, J = 8.8 Hz), 6.90 (d, 1H, J = 1.2 Hz), 4.75-4.69 (m, 2H),4.39-4.28 (m, 2H), 3.83 (s, 3H), 3.82-3.73 (m, 1H) 17 2 ¹H NMR (400 MHz,DMSO-d₆) δ 10.62 (s, 1H), 7.91 (s, 413 1H), 7.88-7.76 (m, 5H), 6.79 (d,J = 1.7 Hz, 1H), 4.89- 4.62 (m, 2H), 4.54-4.18 (m, 3H), 3.76 (s, 3H),2.31 (s, 3H) 18 2 ¹H NMR (400 MHz, DMSO-d₆) δ 10.60 (s, 1H), 7.85- 4137.76 (m, 5H), 7.64 (s, 1H), 6.78 (d, J = 1.7 Hz, 1H), 4.87- 4.62 (m,2H), 4.48-4.23 (m, 2H), 3.87-3.78 (m, 1H), 3.75 (s, 3H), 2.39 (s, 3H) 192 ¹H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 7.99 (s, 413 1H), 7.92 (d,J = 1.6 Hz, 1H), 7.80 (s, 1H), 7.77 (d, J = 0.8 Hz, 1H), 7.74-7.69 (m,2H), 7.61 (dd, J = 8.6, 2.0 Hz, 1H), 6.89 (d, J = 1.6 Hz, 1H), 4.83-4.58(m, 2H), 4.48- 4.26 (m, 2H), 3.83 (s, 4H), 2.44 (s, 3H). 20 1 ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 10.36 (s, 1H), 8.00 413 (s, 1H), 7.93 (s, 1H),7.86-7.78 (m, 6H), 6.88 (s, 1H), 4.93 (br. s., 1H), 4.50-4.41 (m, 2H),4.07-3.98 (br. s., 1H), 3.83 (s, 3H), 1.59 (s, 3H) 21 2 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.62 (t, 1H, J = 6.0 414 Hz), 8.37 (d, 1H, J = 1.6 Hz),8.06 (d, 1H, J = 1.6 Hz), 7.80 (s, 1H), 7.78 (dd, 1H, J = 8.8, 2.4 Hz),7.17 (d, 2H, J = 8.4 Hz), 7.13 (d, 2H, J = 8.4 Hz), 6.99 (d, 1H, J = 1.2Hz), 6.47 (d, 1H, J = 8.4 Hz), 5.96 (s, 2H), 4.75-4.62 (m, 2H),4.34-4.17 (m, 4H), 3.64-3.60 (m, 1H), 2.28 (s, 3H) 22 2 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.58 (br.s, 1H), 416 8.17 (s, 1H), 7.84-7.81 (m, 3H),7.22-7.09 (m, 7H), 4.73- 4.26 (m, 3H), 3.62 (br.s, 1H), 2.26 (s, 3H) 231 ¹H-NMR (500 MHz, CDCl₃) δ ppm 7.86 (s, 1H), 7.68 (s, 416 1H), 7.65 (d,1H, J = 1.0 Hz), 7.55 (s, 1H), 7.25 (d, 2H, J = 8.0 Hz), 7.20 (d, 2H, J= 8.5 Hz), 6.58 (s, 1H), 5.76 (d, 1H, J = 7.5 Hz), 5.21-5.15 (m, 1H),4.65-4.63 (br, 4H), 3.96 (s, 3H), 3.52-3.46 (m, 1H), 2.37 (s, 3H), 1.55(d, 3H, J = 6.5 Hz) 24 2 ¹H NMR (400 MHz, DMSO-d6) δ 8.59 (t, J = 5.9Hz, 1H), 416 7.81 (d, J = 1.6 Hz, 1H), 7.80 (s, 1H), 7.64 (s, 1H), 7.21-7.08 (m, 4H), 6.77 (d, J = 1.7 Hz, 1H), 4.78-4.53 (m, 2H), 4.39-4.13 (m,4H), 3.75 (s, 3H), 3.61 (ddd, J = 14.3, 8.7, 5.6 Hz, 1H), 2.38 (s, 3H),2.26 (s, 3H) 25 2 ¹H NMR (400 MHz, DMSO-d6) δ 8.58 (t, J = 5.8 Hz, 1H),416 7.90 (s, 1H), 7.80 (s, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.21- 7.08 (m,4H), 6.76 (d, J = 1.7 Hz, 1H), 4.73-4.53 (m, 2H), 4.27 (d, J = 5.8 Hz,4H), 3.75 (s, 3H), 3.65-3.57 (m, 1H), 2.29 (s, 3H), 2.27 (s, 3H). 26 1¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.54 (t, 1H, J = 6.0 416 Hz), 8.00 (s,1H), 7.91 (d, 1H, J = 1.6 Hz), 7.79 (s, 1H), 7.77 (s, 1H), 7.15 (d, 2H,J = 8.4 Hz), 7.12 (d, 2H, J = 8.0 Hz), 6.86 (d, 1H, J = 1.6 Hz),4.81-4.78 (br, 1H), 4.35- 4.31 (br, 2H), 4.28 (d, 2H, J = 5.6 Hz),3.98-3.95 (br, 1H), 3.83 (s, 3H), 2.26 (s, 3H), 1.59 (s, 3H) 27 2 ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 12.24-12.20 (br, 416 1H), 8.62 (t, 1H, J = 5.6Hz), 7.83 (s, 1H), 7.73 (s, 1H), 7.18-7.14 (m, 4H), 6.66 (s, 1H),4.73-4.61 (m, 2H), 4.34- 4.21 (m, 2H), 4.28 (d, 2H, J = 5.6 Hz),3.64-3.60 (m, 1H), 2.27 (s, 9H) 28 1 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm8.60 (t, 1H, J = 6.0 416 Hz), 8.01 (s, 1H), 7.98 (s, 1H), 7.85 (s, 1H),7.78 (s, 1H), 7.19-7.14 (m, 4H), 6.98 (s, 1H), 4.28 (d, 2H, J = 5.6 Hz),3.83 (s, 1H), 3.67-3.60 (m, 1H), 2.56 (q, 2H, J = 7.6 Hz), 1.14 (t, 3H,J = 7.6 Hz) 29 3 ¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (t, J = 5.9 Hz, 1H),417 7.85 (d, J = 1.6 Hz, 1H), 7.77 (s, 1H), 7.70 (s, 1H), 7.19- 7.09 (m,4H), 6.78 (d, J = 1.7 Hz, 1H), 4.68 (m, 4H), 4.27 (m, 3H), 3.60 (s, 3H),2.27 (s, 3H) 30 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.63 (br. s., 1H), 4177.92 (br. s., 1H), 7.78 (br. s., 1H), 7.48 (br. s., 1H), 7.16 (br. s.,4H), 6.78 (br. s., 1H), 5.35 (br. s., 2H), 4.93-4.43 (m, 2H), 4.43-3.99(m, 4H), 3.68-3.51 (m, 4H), 2.28 (s, 3H) 31 1 ¹H-NMR (400 MHz, DMSO-d₆)δ ppm 8.57 (d, 1H, J = 418 8.0 Hz), 8.00 (s, 1H), 7.90 (d, 1H, J = 1.2Hz), 7.78, 7.77 (s, s, 2H), 7.35-7.31 (m, 4H), 7.25-7.22 (m, 1H), 6.87(s, 1H), 4.93-4.88 (m, 2H), 4.71-4.22 (m, 4H), 3.83 (s, 3H), 3.71-3.67(m, 1H), 3.57 (br. s., 2H) 32 1 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.57 (t,1H, J = 5.6 418 Hz), 8.00 (s, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 7.78 (s,1H), 7.21 (d, 2H, J = 8.4 Hz), 6.89 (d, 2H, J = 8.8 Hz), 6.88 (s, 1H),4.83-4.45 (m, 2H), 4.44-4.02 (m, 2H), 4.26 (d, 2H, J = 5.6 Hz), 3.84 (s,3H), 3.73 (s, 3H), 3.66-3.55 (m, 1H) 33 2 ¹H-NMR (400 MHz, CD₃OD) δ ppm8.10 (s, 1H), 7.92 (s, 418 1H), 7.28-6.94 (m, 7H), 6.94 (s, 1H),4.68-4.61 (m, 3H), 4.38 (s, 2H), 3.79 (br.s, 1H), 2.30 (s, 3H), 2.25 (s,3H) 34 2 ¹H-NMR (400 MHz, CD₃OD) δ ppm 8.64 (br.s, 1H), 8.05 418 (s,1H), 7.91 (s, 1H), 7.22-7.13 (m, 5H), 6.73 (s, 1H), 4.65 (br.s, 4H),4.40-4.39 (m, 2H), 3.78 (br.s, 1H), 2.48 (s, 3H), 2.31 (s, 3H) 35 2 ¹HNMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 7.9 Hz, 420 1H), 8.00 (s, 1H),7.91 (d, J = 1.6 Hz, 1H), 7.78 (d, J = 3.6 Hz, 1H), 7.43-7.30 (m, 2H),7.21-7.09 (m, 2H), 6.87 (d, J = 2.1 Hz, 1H), 5.04-4.92 (m, 2H),4.75-4.46 (m, 1H), 4.46-4.04 (m, 2H), 3.84 (s, 3H), 3.68-3.55 (m, 2H),1.37 (d, J = 7.0 Hz, 3H). 36 1 ¹H NMR (400 MHz, DMSO-d6) δ 8.59 (t, J =5.8 Hz, 1H), 420 7.99 (s, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.78 (d, J =1.0 Hz, 1H), 7.77 (d, J = 0.8 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.04-6.94 (m, 2H), 6.87 (d, J = 1.6 Hz, 1H), 4.72-4.49 (m, 2H), 4.38-4.12 (m,4H), 3.83 (s, 3H), 3.61 (m, 1H), 2.28 (s, 3H). 37 1 ¹H NMR (400 MHz,DMSO-d6) δ 8.64 (t, J = 5.9 Hz, 1H), 420 7.99 (s, 1H), 7.91 (d, J = 1.6Hz, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.77 (t, J = 1.1 Hz, 1H), 7.22 (t, J= 7.9 Hz, 1H), 7.06- 6.96 (m, 2H), 6.87 (d, J = 1.7 Hz, 1H), 4.74-4.52(m, 2H), 4.39-4.13 (m, 4H), 3.83 (s, 3H), 3.67-3.58 (m, 1H), 2.19 (s,3H). 38 1 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.86 (s, 1H), 7.67 (d, 422 2H, J= 9.6 Hz), 7.54 (s, 1H), 7.34 (d, 2H, J = 6.8 Hz), 7.28-7.24 (m, 2H),6.59 (s, 1H), 5.93 (br. s., 1H), 4.64 (br. s., 3H), 4.49 (br. s., 2H),3.96 (s, 3H), 3.56-3.53 (m, 1H), 1.64 (br. s., 1H). 39 1 ¹H-NMR (400MHz, DMSO-d₆) δ ppm 8.85 (d, 1H, J = 422 6.8 Hz), 7.99 (s, 1H), 7.89 (s,1H), 7.77 (d, 2H, J = 8.0 Hz), 7.35 (d, 2H, J = 8.0 Hz), 7.28 (d, 2H, J= 8.4 Hz), 6.85 (s, 1H), 4.66 (d, 1H, J = 6.0 Hz), 3.82 (s, 3H), 3.45(s, 2H) 40 1 ¹H NMR (500 MHz, DMSO-d6) δ 8.63 (t, J = 5.8 Hz, 1H), 4247.99 (s, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.77 (d, J = 7.9 Hz, 2H), 7.39(td, J = 8.7, 6.7 Hz, 1H), 7.22 (ddd, J = 10.4, 9.4, 2.6 Hz, 1H),7.11-7.03 (m, 1H), 6.86 (d, J = 1.7 Hz, 1H), 4.82-4.48 (m, 2H),4.44-4.05 (m, 3H), 3.83 (s, 3H), 3.68- 3.56 (m, 1H). 41 1 425 42 2¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.60-8.59 (m, 1H), 425 8.52 (d, 1H, J =4.4 Hz), 7.97 (s, 1H), 7.80 (s, 1H), 7.74 (t, 1H, J = 8.0 Hz), 7.63 (d,1H, J = 16.0 Hz), 7.40 (d, 1H, J = 8.0 Hz), 7.22-7.13 (m, 6H), 7.03 (s,1H), 4.27 (d, 2H, J = 5.2 Hz), 3.65-3.58 (m, 1H), 2.26 (s, 3H) 43 2¹H-NMR (400 MHz, DMSO-d₆) δ ppm 10.62 (s, 1H), 8.11 427 (s, 1H), 7.93(d, 1H, J = 1.2 Hz), 7.83-7.78 (m, 5H), 6.91 (d, 1H, J = 1.2 Hz),4.65-4.43 (m, 5H), 3.85-3.81 (m, 1H), 1.42 (d, 6H, J = 6.4 Hz) 44 1¹H-NMR (400 MHz, DMSO-d₆ + CD₃OD) δ ppm 10.85 (s, 427 1H), 8.71 (d, 1H,J = 6.4 Hz), 7.98 (s, 1H), 7.88 (s, 1H), 7.76 (d, 2H, J = 5.2 Hz), 7.54(d, 1H, J = 8.0 Hz), 7.33 (d, 1H, J = 8.4 Hz), 7.19 (s, 1H), 7.07-7.03(m, 1H), 6.98-6.96 (m, 1H), 6.84 (s, 1H), 4.70 (d, 1H, J = 6.0 Hz), 3.82(s, 3H), 3.54 (s, 2H). 45 1 428 46 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm8.61 (t, 1H, J = 5.6 428 Hz), 8.22 (d, 1H, J = 1.6 Hz), 7.83 (s, 1H),7.38-7.35 (m, 2H), 7.30-7.26 (m, 1H), 7.17-7.12 (m, 5H), 6.82-6.80 (m,1H), 4.70-4.67 (br, 2H), 4.31-4.25 (m, 2H), 4.27 (d, 2H, J = 5.6 Hz),3.81 (s, 3H), 3.65-3.60 (m, 1H), 2.27 (s, 3H) 47 2 ¹H NMR (500 MHz,DMSO-d₆) δ 8.59 (t, J = 5.9 Hz, 1H), 8.11 (s, 1H), 7.91 (d, J = 1.6 Hz,1H), 7.77 (d, J = 6.1 Hz, 2H), 7.18-7.10 (m, 4H), 6.89 (d, J = 1.6 Hz,1H), 4.60 (m, 2H) 4.27 (m, 2H), 4.19 (m, 2H), 3.73-3.57 (m, 2H), 2.27(s, 3H), 1.06-0.99 (m, 2H), 1.00-0.93 (m, 2H) 48 1 ¹H NMR (300 MHz,DMSO-d6) δ 8.60 (t, J = 5.8 Hz, 1H), 428 8.01 (s, 1H), 7.92 (d, J = 1.6Hz, 1H), 7.84-7.75 (m, 2H), 7.15 (d, J = 8.1 Hz, 2H), 7.10-6.99 (m, 2H),6.89 (d, J = 1.7 Hz, 1H), 4.61 (s, 2H), 4.50-4.10 (m, 4H), 3.84 (s, 3H),3.70-3.54 (m, 1H), 1.97-1.81 (m, 1H), 0.97-0.86 (m, 2H), 0.69-0.58 (m,2H). 49 2 ¹H NMR (300 MHz, DMSO-d₆) δ 8.62 (t, J = 5.9 Hz, 1H), 428 7.83(d, J = 1.5 Hz, 1H), 7.81 (s, 2H), 7.22-7.09 (m, 4H), 6.78 (d, J = 1.7Hz, 1H), 4.64 (s, 4H), 4.29 (d, J = 5.8 Hz, 2H), 4.08 (t, J = 7.2 Hz,2H), 3.63 (td, J = 9.1, 8.5, 4.4 Hz, 1H), 3.03 (t, J = 7.3 Hz, 2H), 2.62(q, J = 7.3 Hz, 2H), 2.28 (s, 3H) 50 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm8.65-8.62 (m, 2H), 429 8.23 (d, 1H, J = 1.2 Hz), 8.13 (dd, 1H, J = 8.4,2.4 Hz), 7.84 (s, 1H), 7.18-7.14 (m, 5H), 6.86 (d, 1H, J = 8.8 Hz),4.86-4.55 (m, 2H), 4.45-4.09 (m, 4H), 3.87 (s, 3H), 3.67- 3.58 (m, 1H),2.28 (s, 3H) 51 2 ¹H NMR (400 MHz, DMSO-d6) δ 8.59 (t, J = 6.2 Hz, 1H),429 8.27 (d, J = 3.0 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.90- 7.79 (m,2H), 7.41 (dd, J = 8.7, 3.0 Hz, 1H), 7.22-7.08 (m, 5H), 4.77 (br.s, 1H),4.65 (br.s, 1H), 4.42-4.16 (m, 4H), 3.84 (s, 3H), 3.68-3.57 (m, 1H),2.27 (s, 3H). 52 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.62 (br. s., 1H),429 8.23 (s, 1H), 8.06 (s, 1H), 7.90 (d, 1H, J = 9.6 Hz), 7.81 (s, 1H),7.15 (br.s., 4H), 7.01 (s, 1H), 6.44 (d, 1H, J = 9.2 Hz), 4.67-4.63 (m,2H), 4.34-4.19 (m, 4 H), 3.62 (br. s., 1H), 3.47 (s, 3H), 2.27 (s, 3H)53 1 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.29 (d, 1H, J = 430 8.4 Hz), 8.02(s, 1H), 7.93 (d, 1H, J = 1.2 Hz), 7.81(s, 1H), 7.80 (s, 1H), 7.25-7.19(m, 4H), 6.91 (br. s., 1H), 5.26- 5.23 (m, 1H), 5.10 (br. s., 1H), 4.71(br. s., 2H), 4.46-4.27 (m, 3H), 3.85 (s, 3H), 3.82-3.78 (m, 1H), 3.09(dd, 1H, J = 16.0, 4.8 Hz), 2.82 (d, 1H, J = 16.0 Hz) 54 2 ¹H-NMR (400MHz, DMSO-d₆) δ ppm 8.60 (t, 1H, J = 6.0 430 Hz), 8.11 (s, 1H), 7.91 (d,1H, J = 1.6 Hz), 7.78 (d, 2H, J = 2.0 Hz), 7.16 (d, 2H, J = 8.4 Hz),7.13 (d, 2H, J = 8.4 Hz), 6.90 (d, 1H, J = 1.6 Hz), 4.70-4.19 (m, 7H),3.64-3.60 (m, 1H), 2.27 (s, 3H), 1.43 (d, 6H, J = 6.4 Hz) 55 1 ¹H NMR(400 MHz, DMSO-d₆) δ 8.53 (q, J = 5.3, 4.6 Hz, 430 1H), 8.00 (s, 1H),7.90 (d, J = 1.5 Hz, 1H), 7.78 (d, J = 3.6 Hz, 2H), 7.13 (q, J = 8.1 Hz,4H), 6.88 (d, J = 1.7 Hz, 1H), 4.75 (s, 1H), 4.28 (d, J = 5.9 Hz, 3H),3.98 (s, 1H), 3.83 (s, 3H), 3.03 (s, 1H), 2.25 (s, 3H), 1.99 (q, J = 7.4Hz, 2H), 0.83 (t, J = 7.3 Hz, 3H) 56 1 ¹H-NMR (400 MHz, CDCl₃) δ ppm7.92 (br.s, 1H), 7.78 430 (s, 1H), 7.70 (s, 1H), 7.58 (s, 1H), 7.16(br.s, 4H), 6.90 (s, 1H), 5.10 (br.s., 2H), 4.85-4.83 (m, 2H), 4.58(br.s, 1H), 3.97 (s, 3H), 3.63 (br.s, 1H), 2.33 (s, 3H), 1.86-1.79 (m,2H), 0.89 (t, 3H, J = 7.2 Hz) 57 1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (t,J = 5.9 Hz, 1H), 431 8.38 (s, 1H), 8.08-7.68 (m, 4H), 7.26-6.96 (m, 4H),6.85 (d, J = 1.6 Hz, 1H), 6.59 (s, 1H), 4.82-3.96 (m, 6H), 3.83 (s, 3H),3.04 (s, 4H), 2.26 (s, 3H) 58 2 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.59 (d,1H, J = 432 7.6 Hz), 8.36 (d, 1H, J = 1.6 Hz), 8.04 (d, 1H, J = 1.2 Hz),7.79-7.75 (m, 2H), 7.35 (dd, 2H, J = 8.4, 5.6 Hz), 7.17- 7.12 (m, 2H),6.97 (s, 1H), 6.45 (d, 1H, J = 8.4 Hz), 5.95 (s, 2H), 5.01-4.93 (m, 1H),4.71-4.56 (m, 2H), 4.32-4.12 (m, 2H), 3.64-3.57 (m, 1H), 1.37 (d, 3H, J= 7.2 Hz) 59 1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (t, J = 5.9 Hz, 1H), 4328.01 (s, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.78 (d, J = 3.0 Hz, 1H),7.19-7.08 (m, 4H), 6.87 (d, J = 1.6 Hz, 1H), 5.39 (t, J = 5.3 Hz, 1H),4.70 (s, 1H), 4.49 (d, J = 9.1 Hz, 1H), 4.29 (d, J = 5.8 Hz, 2H), 4.16(s, 1H), 3.83 (s, 3H), 3.79 (d, J = 5.4 Hz, 2H), 2.25 (s, 3H) 60 1 ¹HNMR (400 MHz, DMSO-d₆) δ 8.78 (s, 1H), 8.11-7.67 432 (m, 4H), 7.24-7.03(m, 4H), 6.94 (d, J = 1.7 Hz, 1H), 4.92-4.14 (m, 6H), 3.83 (s, 3H), 3.32(s, 3H), 2.26 (s, 3H) 61 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.59 (t, 1H,J = 5.6 432 Hz), 8.23 (d, 1H, J = 1.2 Hz), 7.83-7.81 (m, 3H), 7.42 (d,2H, J = 8.8 Hz), 7.16-7.11 (m, 5H), 4.27 (br.s, 2H), 3.65- 3.60 (m, 1H),2.26 (s, 3H). 62 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.60-8.57 (m, 1H),432 8.27 (s, 1H), 7.91 (s, 1H), 7.82 (s, 1H), 7.75 (d, 1H, J = 7.6 Hz),7.38 (t, 1H, J = 8.0 Hz), 7.26 (d, 1H, J = 7.6 Hz), 7.16-7.11 (m, 4H),4.75-4.67 (m, 2H), 4.33-4.26 (m, 5H), 3.65-3.54 (m, 1H), 2.26 (s, 3H) 632 ¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (t, J = 5.9 Hz, 1H), 433 7.89 (d, J =1.7 Hz, 1H), 7.86 (s, 1H), 7.20-7.05 (m, 4H), 6.73 (d, J = 1.7 Hz, 1H),4.79-4.56 (m, 2H), 4.27 (m, 4H), 3.61 (tt, J = 8.7, 5.7 Hz, 1H), 2.59(s, 3H), 2.42 (s, 3H), 2.26 (s, 3H) 64 1 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm8.41 (d, 1H, J = 434 7.6 Hz), 8.00 (s, 1H), 7.91 (s, 1H), 7.79 (s, 1H),7.77 (s, 1H), 7.37-7.33 (m, 2H), 7.16-7.12 (m, 2H), 6.85 (s, 1H),4.98-4.95 (m, 1H), 4.78 (br. s., 1H), 4.31 (br. s., 2H), 3.99 (br. s.,1H), 3.83 (s, 3H), 1.58 (s, 3H), 1.37 (d, 3H, J = 7.2 Hz) 65 2 ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 8.59 (d, 1H, J = 434 8.0 Hz), 7.91 (s, 1H),7.81 (s, 1H), 7.78 (d, 1H, J = 2.0 Hz), 7.38-7.34 (m, 2H), 7.18-7.13 (m,2H), 6.76 (s, 1H), 5.00-4.96 (m, 1H), 4.78-4.12 (m, 4H), 3.76 (s, 3H),3.63- 3.60 (m, 1H), 2.30 (s, 3H), 1.37 (d, 3H, J = 7.2 Hz) 66 2 ¹H-NMR(400 MHz, CD₃OD) δ ppm 8.02 (s, 1H), 7.92 434 (br.s, 1H), 7.86 (br.s,1H), 7.79 (br.s, 1H), 7.35-7.32 (m, 2H), 7.25-7.21 (m, 1H), 7.05 (t, 2H,J = 8.4 Hz), 4.73-4.59 (m, 2H), 3.90 (s, 3H), 3.85-3.81 (m, 1H),1.84-1.79 (m, 2H), 0.92 (t, 3H, J = 6.8 Hz) 67 2 ¹H NMR (400 MHz,DMSO-d6) δ 8.83-8.70 (m, 2H), 434 7.89-7.74 (m, 2H), 7.13 (qd, J = 8.7,2.6 Hz, 4H), 6.92- 6.81 (m, 1H), 6.25 (d, J = 2.7 Hz, 1H), 4.79 (br.s,1H), 4.64 (br.s, 1H), 4.44-4.14 (m, 6H), 3.79 (dd, J = 6.4, 4.2 Hz, 2H),2.41 (d, J = 6.0 Hz, 2H), 2.25 (s, 3H) - methoxy peak buried under watersignal 68 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.58 (d, 1H, J = 435 8.0Hz), 7.85 (s, 1H), 7.77 (s, 1H), 7.70 (s, 1H), 7.35 (dd, J = 5.6, 8.0Hz, 2H), 7.17-7.12 (m, 2H), 6.77 (s, 1H), 4.99- 4.95 (m, 1H), 4.79-4.03(m, 6H), 3.63-3.56 (m, 4H), 1.37 (d, 3H, J = 6.8 Hz) 69 2 ¹H NMR (400MHz, DMSO-d6) δ 8.76 (t, J = 6.0 Hz, 1H), 436 8.00 (s, 1H), 7.92 (d, J =1.6 Hz, 1H), 7.86-7.76 (m, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.51 (d, J =7.9 Hz, 2H), 6.88 (d, J = 1.7 Hz, 1H), 4.80-4.53 (m, 2H), 4.46-4.18 (m,4H), 3.84 (s, 3H), 3.71-3.61 (m, 1H). 70 1 1H-NMR (400 MHz, DMSO-d6) δppm 8.61 (t, J = 5.2 436 Hz, 1H), 8.00 (s, 1H), 7.91 (d, 1H, J = 1.2Hz), 7.79 (s, 1H), 7.77 (s, 1H), 7.38 (d, 2H, J = 8.8 Hz), 7.28 (d, 2H,J = 8.4 Hz), 6.86 (d, 1H, J = 1.2 Hz), 4.79 (br. s, 1H), 4.33- 4.29 (m,4H), 3.97 (br. s., 1H), 3.83 (s, 3H), 1.60 (s, 3H) 71 1 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.78 (d, 1H, J = 436 6.8 Hz), 7.98 (s, 1H), 7.88 (s, 1H),7.76 (d, 1H, J = 4.0 Hz), 7.37-7.31 (m, 4H), 6.85 (s, 1H), 4.65 (br.s,1H), 3.82 (s, 3H), 3.63-3.58 (m, 1H), 1.33 (d, 3H, J = 7.2 Hz) 72 2¹H-NMR (400 MHz, DMSO-d₆) δ ppm 12.80 (br. s., 1H), 436 8.57 (d, 1H, J =8.4 Hz), 8.05 (br. s., 1H), 7.93 (d, 1H, J = 1.6 Hz), 7.85 (br. s., 1H),7.78 (s, 1H), 7.39 (d, 2H, J = 8.8 Hz), 7.32 (d, 2H, J = 9.6 Hz), 6.89(s, 1H), 4.76-4.51 (m, 3H), 4.50-4.07 (m, 2H), 3.66-3.61 (m, 1H),1.69-1.64 (m, 2H), 0.83 (t, 3H, J = 7.2 Hz) 73 1 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.01 (s, 1H), 7.88 436 (d, 1H, J = 1.2 Hz), 7.77 (s, 1H),7.75 (s, 1H), 7.40-7.33 (m, 4H), 6.81 (d, 1H, J = 1.2 Hz), 4.57 (br. s.,1H), 4.18 (br. s., 2H), 3.90-3.71 (m, 4H), 3.48-3.45 (m, 1H), 2.92- 2.81(m, 1H), 2.65-2.60 (m, 1H), 2.33 (br. s., 1H), 1.72- 1.63 (m, 1H),1.52-1.43 (m, 1H), 0.73 (t, 3H, J = 7.2 Hz) 74 2 ¹H-NMR (400 MHz,CDCl₃ + CD₃OD) δ ppm 7.82 (d, 2H, 438 J = 11.2 Hz), 7.48 (d, 2H, J = 8.0Hz), 7.21-7.18 (m, 4H), 7.11 (d, 2H, J = 7.6 Hz), 6.76 (s, 1H), 6.24(br.s, 1H), 4.46 (d, 2H, J = 4.4 Hz), 2.35 (s, 3H), 1.36-1.32 (m, 1H),1.00- 0.98 (m, 2H), 0.73-0.72 (m, 2H) 75 2 ¹H-NMR (400 MHz, DMSO-d₆) δppm 8.67 (br. s., 1H), 440 8.55 (s, 1H), 8.47 (s, 1H), 8.20 (d, J = 9.6Hz, 1H), 8.10 (d, J = 9.6 Hz, 1H), 7.89 (s, 1H), 7.47 (s, 1H), 7.19-7.14(m, 4H), 4.80-4.72 (m, 2H), 4.48-4.24 (m, 4H), 3.68-3.35 (m, 1H), 2.28(s, 3H) 76 1 ¹H NMR (500 MHz, DMSO-d6) δ 8.66 (t, J = 5.8 Hz, 1H), 4407.99 (s, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.81-7.74 (m, 2H), 7.46-7.33 (m,2H), 7.28 (dd, J = 8.3, 2.1 Hz, 1H), 6.86 (d, J = 1.7 Hz, 1H), 4.63 (d,J = 50.3 Hz, 2H), 4.42-4.09 (m, 4H), 3.83 (s, 3H), 3.67-3.57 (m, 1H). 771 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.86 (d, 1H, J = 6.4 440 Hz), 7.99 (s,1H), 7.90 (s, 1H), 7.76 (d, 2H, J = 6.4 Hz), 7.38-7.34 (m, 2H), 7.23 (d,1H, J = 8.0 Hz), 6.86 (s, 1H), 4.81 (br.s, 1H), 4.68 (br.s, 1H),4.46-4.07 (m, 3H), 3.81 (s, 3H), 3.51 (s, 2H) 78 1 ¹H-NMR (400 MHz,CD₃OD) δ ppm 8.05 (d, 1H, J = 1.2 441 Hz), 7.94 (s, 1H), 7.89 (s, 1H),7.81 (s, 1H), 7.68 (d, 2H, J = 8.4 Hz), 7.48 (d, 2H, J = 8.8 Hz), 7.27(s, 1H), 5.00 (br.s, 2H), 4.72-4.69 (m, 2H), 3.99-3.93 (m, 1H), 3.90 (s,3H), 1.70 (s, 6H) 79 2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.16(d, J = 442 0.8 Hz, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.87-7.66 (m, 2H),7.23-7.04 (m, 4H), 6.90 (d, J = 1.6 Hz, 1H), 4.94-4.01 (m, 7H), 3.62(tt, J = 8.7, 5.6 Hz, 1H), 2.46-2.31 (m, 4H), 2.27 (s, 3H), 1.93-1.67(m, 2H) 80 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.61 (t, 1H, J = 6.0 442Hz), 8.54 (d, 1H, J = 2.4 Hz), 8.10 (d, 1H, J = 2.0 Hz), 7.90 (dd, 1H, J= 2.4, 8.8 Hz), 7.80 (s, 1H), 7.16 (d, 2H, J = 8.4 Hz), 7.12 (d, 2H, J =8.0 Hz), 7.02 (d, 1H, J = 1.6 Hz), 7.66 (d, 1H, J = 8.8 Hz), 4.74-4.21(m, 6H), 3.65-3.58 (m, 1H), 3.03 (s, 6H), 2.27 (s, 3H) 81 3 ¹H-NMR (400MHz, DMSO-d₆) δ ppm 10.64 (s, 1H), 8.01 443 (s, 1H), 7.95 (d, 1H, J =1.2 Hz), 7.79-7.84 (m, 6H), 6.91 (d, 1H, J = 1.2 Hz), 4.95 (d, 1H, J =4.4 Hz), 4.21-4.84 (m, 4H), 3.98 (s, 3H), 3.83 (dd, 1H, J = 2.8 Hz),1.04 (d, 3H, J = 5.6 Hz) 82 2 ¹H-NMR (400 MHz, CD₃OD) δ ppm 8.43 (s,1H), 8.17 (d, 443 1H, J = 5.6 Hz), 7.91 (s, 1H), 7.54-7.47 (m, 2H), 7.42(s, 1H), 7.20-7.12 (m, 4H), 5.07 (d, 1H, J = 7.2 Hz), 4.66 (br.s, 1H),4.57 (d, 1H, J = 8.8 Hz), 4.39 (s, 2H), 4.24 (br.s, 1H), 4.08 (s, 3H),2.30 (s, 3H), 1.72 (s, 3H) 83 1 444 84 1 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm8.60 (t, 1H, J = 5.6 444 Hz), 8.0 (s, 1H), 7.91 (d, 1H, J = 1.6 Hz),7.79 (s, 1H), 7.78 (s, 1H), 7.35 (d, 2H, J = 8.4 Hz), 7.20 (d, 2H, J =8.0 Hz), 6.88 (d, 1H, J = 1.2 Hz), 4.71-4.62 (m, 2H), 4.41-4.20 (m, 4H),3.83 (s, 3H), 3.66-3.57 (m, 1H), 1.26 (s, 9H) 85 2 ¹H NMR (400 MHz,DMSO-d6) δ 8.63 (t, J = 5.9 Hz, 1H), 444 8.22 (d, J = 0.8 Hz, 1H), 7.96(d, J = 1.6 Hz, 1H), 7.82 (d, J = 0.8 Hz, 1H), 7.81 (s, 1H), 7.24-7.11(m, 4H), 6.95 (d, J = 1.6 Hz, 1H), 4.80-4.55 (m, 2H), 4.34 (m, 4H),3.71- 3.60 (m, 1H), 2.30 (s, 3H), 1.56 (s, 9H). 86 1 ¹H NMR (400 MHz,DMSO-d₆) δ 8.52 (t, J = 5.9 Hz, 1H), 445 8.01 (s, 1H), 7.93 (d, J = 1.6Hz, 1H), 7.81 (s, 1H), 7.77 (d, J = 0.8 Hz, 1H), 7.52 (s, 2H), 7.31-7.00(m, 4H), 6.86 (d, J = 1.7 Hz, 1H), 4.83 (s, 2H), 4.46 (s, 2H), 4.30 (d,J = 5.8 Hz, 2H), 3.83 (s, 3H), 2.25 (s, 3H) 87 2 ¹H-NMR (400 MHz, CD₃OD)δ ppm 8.00 (d, 1H, J = 8.0 445 Hz), 7.91 (s, 1H), 7.25-7.14 (m, 5H),6.30 (br.s, 1H), 4.39 (s, 2H), 4.21 (d, 2H, J = 2.0 Hz), 3.81-3.73 (m,3H), 2.66- 2.52 (m, 2H), 2.31 (s, 3H), 2.16 (d, 3H, J = 15.2 Hz) 88 1 ¹HNMR (400 MHz, DMSO-d₆) δ 8.95 (s, 1H), 7.99 (s, 445 1H), 7.96-7.91 (m,1H), 7.82 (s, 1H), 7.76 (s, 1H), 7.22- 7.09 (m, 4H), 6.81 (s, 1H), 4.76(s, 1H), 4.55 (s, 1H), 4.32 (d, J = 5.7 Hz, 3H), 4.19 (s, 1H), 3.83 (s,3H), 2.99 (s, 2H), 2.26 (s, 3H) 89 2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.58(t, J = 6.0 Hz, 1H), 445 7.86 (d, J = 1.6 Hz, 1H), 7.80 (s, 1H), 7.77(s, 1H), 7.23- 6.98 (m, 4H), 6.80 (d, J = 1.7 Hz, 1H), 4.94-3.98 (m,8H), 3.73-3.56 (m, 1H), 2.27 (s, 3H), 1.35 (d, J = 6.6 Hz, 6H) 90 1 ¹HNMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 8.4 Hz, 445 1H), 7.99 (s, 1H),7.89 (d, J = 1.6 Hz, 1H), 7.77, 7.76 (2 closely spaced singlets, 2H),7.18 (d, J = 7.7 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 6.86 (s, 1H), 4.91(td, J = 8.4, 6.0 Hz, 1H), 4.77-3.97 (m, 6H), 3.82 (s, 3H), 3.66-3.55(m, 1H), 2.26 (s, 3H), 1.72 (dp, J = 20.0, 6.5 Hz, 2H). 91 2 ¹H-NMR (400MHz, DMSO-d₆) δ ppm 8.60 (t, 1H, J = 5.6 446 Hz), 8.07 (s, 1H),7.82-7.79 (m, 2H), 7.16 (d, 2H, J = 8.0 Hz), 7.13 (d, 2H, J = 7.6 Hz),7.08 (s, 1H), 7.0 (dd, 1H, J = 2.4, 11.2 Hz), 6.82 (ddd, 1H, J = 2.4,8.4, 16.8 Hz), 4.75- 4.65 (m, 2H), 4.35-4.21 (m, 4H), 3.91 (s, 3H),3.64-3.61 (m, 1H), 2.27 (s, 3H) 92 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm8.61 (br. s., 1H), 446 8.19 (s, 1H), 7.82 (s, 1H), 7.71 (d, 1H, J = 12.8Hz), 7.58 (d, 1H, J = 8.8 Hz), 7.16-7.11 (m, 6H), 4.74-4.63 (m, 2H),4.28-4.18 (m, 4H), 3.85 (s, 3H), 3.62 (br. s., 1H), 2.27 (s, 3H) 93 3¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.60 (t, 1H, J = 5.6 446 Hz), 8.01 (s,1H), 7.92 (t, 1H, J = 1.6 Hz), 7.79 (d, 2H, J = 2.8 Hz), 7.15 (d, 2H, J= 8.0 Hz), 7.12 (d, 2H, J = 8.0 Hz), 6.89 (d, 1H, J = 1.2 Hz), 4.94 (d,1H, J = 4.4 Hz), 4.69- 4.20 (m, 6H), 3.98 (s, 3H), 3.63-3.59 (m, 1H),2.28 (s, 3H), 1.04 (d, 3H, J = 5.2 Hz) 94 2 ¹H NMR (400 MHz, DMSO-d6) δ8.49 (d, J = 8.3 Hz, 446 1H), 7.99 (s, 1H), 7.90 (d, J = 1.6 Hz, 1H),7.77 (two closely spaced peaks, 2H), 7.18 (d, J = 8.1 Hz, 2H), 7.12 (d,J = 7.9 Hz, 2H), 6.86 (s, 1H), 4.92 (q, J = 8.6, 8.2 Hz, 1H), 4.75-4.07(m, 6H), 3.83 (s, 3H), 3.60 (ddd, J = 14.4, 8.8, 5.6 Hz, 1H), 2.26 (s,3H), 1.81 (dtd, J = 25.1, 13.6, 7.0 Hz, 2H)-one peak is partially buriedunder water signal. 95 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.60 (d, 1H, J= 448 8.0 Hz), 8.11 (s, 1H), 7.91 (d, 1H, J = 1.6 Hz), 7.78 (d, 2H, J =1.6 Hz), 7.38-7.35 (m, 2H), 7.19-7.13 (m, 2H), 6.89 (s, 1H), 5.00-4.96(m, 1H), 4.75-4.22 (m, 4H), 3.64-3.60 (m, 1H), 1.44 (d, 6H, J = 6.8 Hz),1.38 (d, 3H, J = 7.2 Hz) 96 1 ¹H-NMR (400 MHz, DMSO-d₆ + CD₃OD) δ ppm7.97 (s, 448 1H), 7.86 (s, 1H), 7.74 (d, 2H, J = 4.8 Hz), 7.66 (d, 1H, J= 7.2 Hz), 7.38-7.33 (m, 4H), 6.80 (s, 1H), 4.80-4.71 (m, 1H), 4.35(br.s, 2H), 3.82 (s, 3H), 1.36 (d, 2H, J = 2.4 Hz), 0.98 (s, 2H). 97 1¹H NMR (400 MHz, DMSO-d₆) δ 8.53 (d, J = 8.1 Hz, 1H), 448 8.00 (s, 1H),7.91 (d, J = 1.6 Hz, 1H), 7.82-7.75 (m, 2H), 7.32 (d, J = 1.6 Hz, 1H),7.24 (d, J = 1.2 Hz, 2H), 6.89 (d, J = 1.6 Hz, 1H), 5.30 (q, J = 7.9 Hz,1H), 4.66-4.24 (m, 4H), 3.84 (s, 3H), 3.59 (tt, J = 8.6, 5.7 Hz, 1H),3.00-2.75 (m, 2H), 2.42 (m, 1H), 1.83 (m, 1H) 98 3 ¹H-NMR (400 MHz,CD₃OD) δ ppm 7.94 (br.s, 1H), 7.79 450 (s, 1H), 7.76 (d, 1H, J = 2.0Hz), 7.71 (s, 1H), 7.37-7.34 (m, 2H), 7.05 (t, 2H, J = 8.4 Hz), 6.85 (s,1H), 5.06-5.03 (m, 1H), 4.24 (t, 2H, J = 6.4 Hz), 3.90 (t, 2H, J = 6.4Hz), 3.69-3.63 (m, 1H), 1.47 (d, 3H, J = 6.8 Hz) 99 1 ¹H NMR (400 MHz,DMSO-d6) δ 8.55 (d, J = 8.2 Hz, 450 1H), 7.99 (s, 1H), 7.90 (d, J = 1.6Hz, 1H), 7.77 (d, J = 3.3 Hz, 2H), 7.43-7.36 (m, 2H), 7.36-7.27 (m, 2H),6.86 (s, 1H), 4.73 (q, J = 7.6 Hz, 1H), 4.61-4.05 (m, 4H), 3.83 (s, 3H),3.63 (tt, J = 8.7, 5.7 Hz, 1H), 1.68 (p, J = 7.3 Hz, 2H), 0.83(t, J =7.3 Hz, 3H). 100 2 ¹H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J = 7.8 Hz, 4501H), 8.01 (s, 1H), 7.92 (d, J = 1.6 Hz, 1H), 7.79 (d, J = 5.7 Hz, 2H),7.43-7.31 (m, 4H), 6.86 (d, J = 1.7 Hz, 1H), 4.97 (q, J = 7.1 Hz, 1H),4.47-3.91 (m, 4H), 3.84 (s, 3H), 1.59 (s, 3H), 1.38 (d, J = 7.0 Hz, 3H).101 2 ¹H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 8.4 Hz, 452 1H), 7.98 (s,1H), 7.92 (s, 1H), 7.78 (d, J = 9.1 Hz, 2H), 7.38 (s, 4H), 7.09 (s, 1H),6.89 (d, J = 4.5 Hz, 1H), 4.99 (m, 1H), 4.80 (d, J = 39.7 Hz, 1H),4.50-4.31 (m, 2H), 4.14-4.03 (m, 1H), 3.83 (s, 3H), 1.41 (d, J = 7.0 Hz,3H). 102 1 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.89 (t, 1H, J = 6.4 452 Hz),8.00 (s, 1H), 7.95 (d, 1H, J = 1.2 Hz), 7.82 (s, 1H), 7.78 (s, 1H),7.39-7.37 (m, 2H), 7.31-7.29 (d, 2H, J = 8.4 Hz), 6.94 (d, 1H, J = 1.6Hz), 4.81, 4.64 (br. s., 2H), 4.34, 4.24 (br. s., 2H), 4.32 (d, 2H, J =6.0 Hz), 3.84 (s, 3H), 3.33 (s, 3H) 103 1 ¹H-NMR (400 MHz, DMSO-d₆) δppm 8.61 (d, 1H, J = 452 6.8 Hz), 8.00 (s, 1H), 7.92 (s, 1H), 7.79 (br.s., 2H), 7.49- 7.35 (m, 4H), 6.88 (s, 1H), 4.98-4.91 (m, 2H), 4.70-4.10(m, 4H), 3.84 (s, 3H), 3.69 (br. s., 1H), 3.57 (br. s., 2H) 104 1 ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 10.33 (s, 1H), 8.00 453 (s, 1H), 7.92 (d, 1H, J= 1.5 Hz), 7.81 (s, 1H), 7.78 (s, 1H), 7.60 (d, 2H, J = 8.8 Hz), 7.50(d, 2H, J = 9.2 Hz), 6.89 (d, 1H, J = 1.6 Hz), 4.75-4.28 (m, 4H), 3.83(s, 3H), 3.80-3.74 (m, 1H) 105 2 ¹H NMR (400 MHz, DMSO-d6) δ 8.61 (t, J= 5.9 Hz, 1H), 453 8.49 (s, 1H), 8.30 (d, J = 1.7 Hz, 1H), 8.00 (s, 1H),7.92 (dd, J = 7.9, 1.5 Hz, 1H), 7.84 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H),7.23 (d, J = 1.7 Hz, 1H), 7.20-7.09 (m, 4H), 4.84- 4.64 (m, 2H),4.43-4.16 (m, 6H), 3.63 (m, 1H), 2.27 (s, 3H). 106 2 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 10.59 (s, 1H), 8.09 453 (s, 1H), 7.82-7.77 (m, 4H), 7.66(d, 2H, J = 8.8 Hz), 7.02 (s, 1H), 6.90 (d, 2H, J = 8.8 Hz), 4.80-4.70(m, 2H), 4.64- 4.58 (m, 1H), 4.41-4.32 (m, 2H), 3.83-3.80 (m, 1H), 1.24(d, 6H, J = 5.6 Hz) 107 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 10.60 (s, 1H),8.15 453 (s, 1H), 7.83-7.77 (m, 4H), 7.68 (d, 2H, J = 8.4 Hz), 7.44 (d,2H, J = 8.0 Hz), 7.08 (s, 1H), 4.96 (s, 1H), 4.80-4.70 (m, 2H),4.42-4.30 (m, 2H), 3.82-3.81 (m, 1H), 1.41 (s, 6H) 108 2 ¹H NMR (400MHz, DMSO-d6) δ 8.60 (t, J = 5.9 Hz, 1H), 454 8.15 (d, J = 1.7 Hz, 1H),7.81 (s, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H),7.21-7.10 (m, 4H), 7.07 (d, J = 1.8 Hz, 1H), 4.84-4.58 (m, 2H), 4.28 (d,J = 5.8 Hz, 4H), 3.63 (m, 1H), 2.27 (s, 3H), 0.93 (d, J = 15.0 Hz, 4H).109 2 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.89 (d, 2H, J = 9.6 454 Hz), 7.48(d, 2H, J = 8.4 Hz), 7.18-7.07 (m, 7H), 6.87 (br.s, 1H), 5.16 (br.s,1H), 4.96 (br.s, 1H), 4.82 (br.s, 1H), 4.69 (br.s, 1H), 4.42 (br.s, 2H),3.77-3.76 (m, 1H), 3.75- 3.71 (m, 1H), 2.29 (s, 3H), 0.80 (d, 4H, J =6.0 Hz) 110 2 ¹H NMR (300 MHz, DMSO-d₆) δ 8.61 (t, J = 5.7 Hz, 1H), 4548.01 (s, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.83-7.74 (m, 2H), 7.49-7.23 (m,3H), 6.87 (d, J = 1.7 Hz, 1H), 4.92-4.65 (m, 2H), 4.49-4.25 (m, 4H),4.06-3.93 (m, 1H), 3.84 (s, 3H), 1.60 (s, 3H) 111 2 455 112 2 ¹H NMR(400 MHz, DMSO-d6) δ 8.76 (t, J = 6.0 Hz, 1H), 456 8.00 (s, 1H), 7.92(d, J = 1.6 Hz, 1H), 7.86-7.76 (m, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.51(d, J = 7.9 Hz, 2H), 6.88 (d, J = 1.7 Hz, 1H), 4.80-4.53 (m, 2H),4.46-4.18 (m, 4H), 3.84 (s, 3H), 3.71-3.61 (m, 1H). 113 2 ¹H-NMR (400MHz, DMSO-d₆) δ ppm 8.59 (t, 1H, J = 6.0 456 Hz), 8.09 (s, 1H), 7.80 (s,1H), 7.31 (d, 1H, J = 2.4 Hz), 7.23 (d, 1H, J = 2.0 Hz), 7.17-7.12 (m,4H), 7.02 (s, 1H), 6.85 (d, 1H, J = 8.4 Hz), 4.29-4.27 (m, 4H), 4.25 (s,2H), 3.64-3.56 (m, 1H), 2.27 (s, 3H) 114 2 ¹H-NMR (400 MHz, CD₃OD) δ ppm8.69 (d, 1H, J = 7.6 456 Hz), 8.14 (s, 1H), 7.86 (s, 1H), 7.56 (d, 2H, J= 7.6 Hz), 7.39-7.35 (m, 3H), 7.11-7.03 (m, 4H), 5.09-5.04 (m, 1H),4.98-4.92 (m, 2H), 4.60-4.46 (m, 2H), 3.78-3.76 (m, 1H), 1.93-1.90 (m,1H), 1.48 (d, 3H, J = 6.8 Hz), 0.99-0.97 (m, 2H), 0.70-0.68 (m, 2H) 1152 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.60 (t, 1H, J = 5.6 456 Hz), 8.10 (d,1H, J = 0.8 Hz), 7.81 (s, 1H), 7.68 (d, 2H, J = 8.8 Hz), 7.16 (d, 2H, J= 8.8 Hz), 7.13 (d, 2H, J = 8.80 Hz), 7.02 (s, 1H), 8.92 (d, 2H, J = 8.8Hz), 4.75-4.19 (m, 7H), 3.66-3.59 (m, 1H), 2.27 (s, 3H), 1.27 (d, 6H, J= 6.0 Hz) 116 2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (t, J = 5.9 Hz, 1H),456 8.17 (d, J = 1.6 Hz, 1H), 7.85-7.78 (m, 2H), 7.59 (dt, J = 7.4, 1.5Hz, 1H), 7.39-7.25 (m, 2H), 7.20-7.04 (m, 5H), 4.99 (s, 1H), 4.68 (s,2H), 4.28 (d, J = 5.8 Hz, 2H), 4.21 (s, 1H), 3.69-3.57 (m, 1H), 2.27 (s,3H), 1.46 (s, 6H) 117 2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (t, J = 5.9 Hz,1H), 8.15 (d, J = 1.6 Hz, 1H), 7.8 (s, 1H), 7.74-7.66 (m, 2H), 7.49-7.42(m, 2H), 7.20-7.09 (m, 4H), 7.07 (d, J = 1.7 Hz, 1H), 4.98 (s, 1H), 4.76(s, 1H), 4.67 (s, 2H), 4.35 (s, 1H), 4.28 (d, J = 5.8 Hz, 2H), 4.22 (s,1H), 3.68-3.56 (m, 1H), 2.27 (s, 3H), 1.43 (s, 6H) 118 2 ¹H-NMR (400MHz, CDCl₃ + CD₃OD) δ ppm 7.75 (s, 1H), 456 7.70 (s, 1H), 7.48-7.43 (m,4H), 7.13-7.08 (m, 4H), 6.71 (s, 1H), 4.76 (br.s, 1H), 3.47 (s, 2H),2.27 (s, 3H), 1.52 (s, 6H) 119 1 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.76 (s,1H), 7.59 (s, 456 1H), 7.55 (s, 1H), 7.45 (s, 1H), 7.10 (d, 2H, J = 7.6Hz), 6.99 (d, 2H, J = 8.0 Hz), 6.48 (s, 1H), 5.60 (d, 1H, J = 8.4 Hz),4.82 (d, 1H, J = 7.6 Hz), 4.51 (br.s, 4H), 3.87 (s, 3H), 3.40 (d, 1H, J= 8.4 Hz), 1.82-1.73 (m, 3H), 0.89 (d, 2H, J = 7.2 Hz), 0.83 (t, 3H, J =7.2 Hz), 0.61 (d, 1H, J = 4.4 Hz) 120 1 ¹H NMR (500 MHz, DMSO-d6) δ 8.68(t, J = 5.8 Hz, 1H), 456 7.99 (s, 1H), 7.91 (d, J = 1.6 Hz, 1H),7.82-7.74 (m, 2H), 7.61 (d, J = 2.1 Hz, 1H), 7.43 (dd, J = 8.3, 2.1 Hz,1H), 7.38 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 1.6 Hz, 1H), 4.65 (d, J =47.0 Hz, 2H), 4.41-4.14 (m, 3H), 3.83 (s, 3H), 3.72- 3.61 (m, 2H). 121 1¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.84 (d, 1H, J = 456 6.0 Hz), 8.00 (s,1H), 7.94 (s, 1H), 7.82 (s, 1H), 7.78 (s, 1H), 7.57 (s, 1H), 7.39 (s,2H), 6.93 (s, 1H), 4.69 (br.s, 1H), 3.82 (s, 3H), 3.70-3.63(m, 6H). 1223 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.62 (t, 1H, J = 5.8 457 Hz), 8.13 (s,1H), 7.92 (s, 1H), 7.80 (s, 2H), 7.16 (d, 2H, J = 8.0 Hz), 7.13 (d, 2H,J = 8.0 Hz), 6.90 (d, 1H, J = 1.6 Hz), 4.80-4.49 (m, 3H), 4.35-4.20 (m,4H), 3.68-3.58 (m, 1H), 3.18-3.10 (m, 1H), 3.07-2.99 (m, 1H), 2.98-2.91(m, 1H), 2.89-2.79 (m, 1H), 2.28 (s, 3H), 2.23-2.12 (m, 1H), 2.06-1.96(m, 1H) 123 1 ¹H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.01 (s, 4581H), 7.94 (d, J = 1.6 Hz, 1H), 7.82 (s, 1H), 7.79 (d, J = 0.8 Hz, 1H),7.78-7.72 (m, 2H), 7.35 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 1.6 Hz, 1H),4.84-4.63 (br.m, 2H), 4.48-4.24 (br.m, 2H), 3.84 (s, 4H). 124 2 ¹H-NMR(400 MHz, CD₃OD) δ ppm 8.65 (d, 1H, J = 7.6 458 Hz), 7.87 (s, 1H), 7.83(s, 1H), 7.37-7.34 (m, 2H), 7.07- 7.03 (m, 3H), 6.22 (br.s, 1H),5.07-5.04 (m, 1H), 4.58 (br.s, 4H), 4.10 (s, 2H), 3.73 (br.s, 1H), 3.72(s, 3H), 3.69- 3.68 (m, 2H), 2.51 (br.s, 2H), 1.47 (d, 2H, J = 6.8 Hz).125 2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (t, J = 5.9 Hz, 1H), 458 8.16 (d,J = 1.6 Hz, 1H), 7.82 (d, J = 1.2 Hz, 1H), 7.76- 7.66 (m, 2H), 7.33 (d,J = 8.0 Hz, 2H), 7.22-7.11 (m, 4H), 7.08 (d, J = 1.7 Hz, 1H), 5.20 (d, J= 4.3 Hz, 1H), 4.90-4.01 (m, 7H), 3.71-3.55 (m, 1H), 3.43 (t, J = 5.9Hz, 2H), 2.27 (s, 3H) 126 2 ¹H NMR (300 MHz, DMSO-d₆) δ 8.61 (t, J = 5.9Hz, 1H), 459 7.89-7.73 (m, 2H), 7.27-7.07 (m, 4H), 6.82 (d, J = 1.9 Hz,1H), 6.22 (d, J = 4.2 Hz, 1H), 4.65 (m, 2H), 4.41- 4.04 (m, 6H), 3.64(m, 3H), 2.45-2.34 (m, 2H), 2.28 (s, 3H), 1.08-0.94 (m, 3H) 127 2 ¹H NMR(400 MHz, DMSO-d6) δ 8.59 (q, J = 5.1 Hz, 459 1H), 7.96-7.77 (m, 2H),7.23-7.05 (m, 4H), 6.81 (dd, J = 26.1, 1.7 Hz, 1H), 6.41-6.30 (m, 1H),4.65 (br.d, J = 36.3 Hz, 2H), 4.27 (m, 6H), 3.58 (ddd, J = 20.0, 10.8,4.5 Hz, 3H), 2.41 (m, 2H), 2.27 (m, 4H), 2.19 (br.s, 1H), 1.01 (td, J =7.4, 4.2 Hz, 3H). 128 1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (t, J = 5.8 Hz,1H), 8.02 (s, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.78 (d, J = 0.9 Hz, 2H),7.29-7.01 (m, 4H), 6.89 (d, J = 1.6 Hz, 1H), 5.03- 3.91 (m, 6H), 3.83(s, 3H), 2.91 (d, J = 23.4 Hz, 2H), 2.26 (s, 3H), 2.17 (s, 6H) 129 2 ¹HNMR (300 MHz, DMSO-d6) δ 8.44 (d, J = 7.8 Hz, 460 1H), 7.81 (m, 3H),7.44-7.28 (m, 2H), 7.23-7.08 (m, 2H), 6.74 (d, J = 1.7 Hz, 1H), 4.97 (m,1H), 4.78 (s, 1H), 4.36 (d, J = 4.2 Hz, 2H), 4.07 (t, J = 7.2 Hz, 3H),3.03 (t, J = 7.3 Hz, 2H), 2.60 (m, 2H), 1.59 (s, 3H), 1.39 (d, J = 7.0Hz, 3H). 130 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.61 (t, 1H, J = 5.6 460Hz), 7.99 (s, 1H), 7.94 (s, 1H), 7.79 (d, 2H, J = 2.0 Hz), 7.15 (d, 2H,J = 8.0 Hz), 7.12 (d, 2H, J = 8.0 Hz), 6.90 (s, 1H), 4.72-4.18 (m, 7H),3.99 (s, 2H), 3.63-3.60 (m, 1H), 2.27 (s, 3H), 1.07 (s, 6H) 131 2 ¹H-NMR(400 MHz, CD₃OD) δ ppm 8.11 (s, 1H), 8.01 (s, 460 1H), 7.91 (s, 1H),7.85 (s, 1H), 7.32 (s, 1H), 7.20-7.12 (m, 4H), 4.76-4.74 (m, 1H), 4.11(s, 2H), 3.53 (s, 2H), 2.30 (s, 3H), 1.19 (s, 6H) 132 3 ¹H-NMR (400 MHz,CD₃OD) δ ppm 8.63 (br.s, 1H), 8.13 460 (s, 1H), 8.02 (s, 1H), 7.84 (d,2H, J = 3.6 Hz), 7.23-7.13 (m, 5H), 4.39 (d, 2H, J = 4.8 Hz), 3.75 (s,3H), 2.31 (s, 3H), 1.58 (s, 6H) 133 2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.86(t, J = 5.8 Hz, 1H), 460 7.85 (d, J = 1.6 Hz, 1H), 7.77 (s, 1H), 7.69(s, 1H), 7.31- 6.84 (m, 4H), 6.76 (d, J = 1.7 Hz, 1H), 4.70 (m, 3H),4.47 (s, 1H), 4.28 (m, 3H), 4.10 (s, 1H), 3.60 (s, 3H), 3.31 (s, 5H),3.01 (s, 2H), 2.32 (s, 3H), 2.26 (s, 3H) 134 2 ¹H NMR (400 MHz, DMSO-d₆)δ 8.58 (t, J = 5.9 Hz, 1H), 461 7.87-7.72 (m, 2H), 7.22-7.06 (m, 4H),6.80 (d, J = 1.7 Hz, 1H), 6.20 (s, 1H), 4.74-4.49 (m, 2H), 4.36-4.13 (m,4H), 4.02 (br.s, 2H), 3.59 (m, 6H), 2.46-2.40 (m, 2H), 2.27 (s, 3H) 1352 461 136 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.60 (d, 1H, J = 462 8.0Hz), 8.28 (s, 1H), 7.95 (d, 2H, J = 1.6 Hz), 7.80 (s, 1H), 7.38-7.35 (m,2H), 7.18-7.14 (m, 2H), 6.94 (s, 1H), 5.57-5.54 (m, 1H), 5.00-4.87 (m,5H), 4.72-4.16 (m, 4H), 3.64-3.61 (m, 1H), 1.38 (d, 3H, J = 7.2 Hz) 1372 ¹H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 7.8 Hz, 462 1H), 8.18 (s,1H), 7.92 (d, J = 1.6 Hz, 1H), 7.78 (d, J = 5.8 Hz, 2H), 7.39-7.29 (m,2H), 7.20-7.09 (m, 2H), 6.90 (d, J = 1.8 Hz, 1H), 4.97 (m, 1H),4.74-4.06 (m, 4H), 3.61 (tt, J = 8.7, 5.6 Hz, 1H), 1.53 (s, 9H), 1.36(d, J = 6.9 Hz, 3H). 138 1 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.74-7.72 (m,3H), 462 7.58 (s, 1H) 7.55-7.40 (m, 1H) 7.24-7.15 (m, 4H), 6.95 (d, 1H,J = 5.6 Hz), 5.03-4.75 (m, 2H), 4.71-4.73 (m, 1H), 4.59-4.50 (m, 1H),4.23-4.15 (m, 1H) 3.93 (s, 3H), 3.80- 3.68 (m, 1H), 1.09 (br.s, 1H),0.53 (br.s, 2H), 0.31-0.25 (m, 2H) 139 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm8.57 (d, 1H, J = 462 8.4 Hz), 8.37 (s, 1H), 8.05 (s, 1H), 7.83-7.72 (m,2H), 7.39 (d, 2H, J = 8.4 Hz), 7.33 (d, 2H, J = 8.4 Hz), 6.98 (s, 1H),6.46 (d, 1H, J = 8.4 Hz), 5.96-5.91 (m, 2H), 4.78-4.50 (m, 3H),4.50-4.00 (m, 2H), 3.70-3.65 (m, 1H), 1.74-1.62 (m, 2H), 0.85 (t, 3H, J= 7.2 Hz) 140 2 ¹H-NMR (400 MHz, CD₃OD) δ ppm 7.92 (s, 1H), 7.78 (s, 4642H), 7.72 (s, 1H), 7.35-7.32 (m, 2H), 7.06 (t, 2H, J = 8.8 Hz), 6.86 (d,1H, J = 2.0 Hz), 4.40 (s, 2H), 4.10 (s, 2H), 3.69-3.66 (m, 1H), 1.19 (s,6H) 141 2 ¹H-NMR (400 MHz, CD₃OD) δ ppm 8.70 (d, 1H, J = 7.6 464 Hz),8.06 (s, 1H), 7.99 (s, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 7.38-7.35 (m,2H), 7.27 (br.s, 1H), 7.06 (t, 2H, J = 8.8 Hz), 5.08-5.05 (m, 1H),4.95-4.90 (m, 2H), 4.63-4.48 (m, 2H), 4.33-4.30 (m, 2H), 3.76-3.74 (m,3H), 3.04 (s, 3H), 1.48 (d, 3H, J = 6.4 Hz) 142 3 ¹H-NMR (400 MHz,CD₃OD) δ ppm 8.72 (d, 1H, J = 8.0 464 Hz), 8.07 (s, 1H), 8.00 (br.s,1H), 7.90-7.84 (m, 2H), 7.38- 7.35 (m, 2H), 7.27 (d, 1H, J = 8.0 Hz),7.05 (t, 2H, J = 8.8 Hz), 5.09-5.04 (m, 1H), 4.97-4.93 (m, 2H),4.66-4.64 (m, 2H), 4.15-4.07 (m, 3H), 3.81-3.78 (m, 1H), 1.48 (d, 3H, J= 4.0 Hz), 1.18 (d, 3H, J = 5.6 Hz) 143 1 ¹H-NMR (400 MHz, DMSO-d₆) δppm 8.32 (d, 1H, J = 464 8.4 Hz), 8.02 (s, 1H), 7.93 (s, 1H), 7.81 (s,1H), 7.79 (s, 1H), 7.32 (s, 1H), 7.25 (s, 1H), 7.18 (s, 1H), 6.90 (br.s., 1H), 5.24-5.19 (m, 2H), 4.75-4.70 (m, 2H), 4.47-4.45 (m, 1H),4.32-4.27 (m, 2H), 3.85 (s, 3H), 3.81-3.77 (m, 1H), 3.07 (dd, 1H, J =16.8, 4.8 Hz), 2.81 (d, 1H, J = 16.0 Hz) 144 2 ¹H NMR (300 MHz, DMSO-d6)δ 8.40 (d, J = 8.1 Hz, 464 1H), 8.01 (s, 1H), 7.92 (d, J = 1.6 Hz, 1H),7.79 (d, J = 4.7 Hz, 2H), 7.47-7.25 (m, 4H), 6.86 (d, J = 1.7 Hz, 1H),4.73 (m, 1H), 4.48-3.94 (m, 4H), 3.84 (s, 3H), 1.71 (qd, J = 7.4, 3.7Hz, 2H), 1.59 (s, 3H), 0.87 (t, J = 7.3 Hz, 3H). 145 2 ¹H NMR (300 MHz,DMSO-d6) δ 8.72 (t, J = 5.9 Hz, 1H), 464 8.38-8.31 (m, 1H), 8.01 (s,1H), 7.92 (d, J = 1.6 Hz, 1H), 7.82-7.76 (m, 2H), 7.59 (ddd, J = 8.1,2.3, 0.9 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 1.7 Hz, 1H),4.73- 4.19 (m, 7H), 3.84 (s, 3H), 3.74-3.62 (m, 1H), 2.28 (s, 3H). 146 2¹H-NMR (400 MHz, CD₃OD) δ ppm 7.96 (s, 1H), 7.75 (s, 464 2H), 7.70 (s,1H), 7.32 (s, 4H), 6.85 (s, 1H), 5.06-5.01 (m, 1H), 4.54-4.49 (m, 2H),3.68-3.65 (m, 1H), 1.51 (d, 6H, J = 6.8 Hz), 1.46 (d, 3H, J = 6.8 Hz)147 2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (t, J = 5.9 Hz, 1H), 465 8.22 (d,J = 1.6 Hz, 1H), 7.90-7.77 (m, 3H), 7.54-7.48 (m, 2H), 7.23-7.04 (m,5H), 4.82-4.63 (m, 2H), 4.40- 4.19 (m, 4H), 3.67-3.58 (m, 1H), 2.27 (s,3H), 1.70 (s, 6H) 148 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.57 (d, 1H, J =465 8.4 Hz), 7.86 (d, 1H, J = 1.6 Hz), 7.77 (s, 1H), 7.71 (s, 1H), 7.39(d, 2H, J = 8.8 Hz), 7.33 (d, 2H, J = 8.4 Hz), 6.78 (s, 1H), 4.83-4.50(m, 5H), 4.45-4.01 (m, 2H), 3.64- 3.58 (m, 1H), 3.61 (s, 3H), 1.73-1.63(m, 2H), 0.84 (t, J = 7.6 Hz, 3H) 149 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm8.57 (d, 1H, J = 465 8.0 Hz), 7.91 (d, 1H, J = 1.2 Hz), 7.77 (s, 1H),7.47 (s, 1H), 7.39 (d, 2H, J = 8.4 Hz), 7.33 (d, 2H, J = 8.4 Hz), 6.77(s, 1H), 5.35-5.32 (m, 2H), 4.83-4.45 (m, 3H), 4.44- 3.40 (m, 2H),3.66-3.60 (m, 1H), 3.57 (s, 3H), 1.74-1.63 (m, 2H), 0.84 (t, J = 7.2 Hz,3H) 150 ¹H NMR (500 MHz, DMSO-d₆) δ 8.68 (d, J = 8.2 Hz, 1H), 8.15 (s,1H), 7.99 (s, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.77 (d, J = 5.3 Hz, 2H),7.42-7.33 (m, 4H), 6.86 (s, 1H), 5.07 (q, J = 7.4 Hz, 1H), 4.0-4.9 (m,4H), 4.58 (s, 1H), 4.34 (s, 2H), 3.83 (s, 3H), 3.72-3.59 (m, 1H),3.62-3.44 (m, 3H), 3.25 (s, 3H), 3.18-3.09 (m, 1H) 151 2 ¹H NMR (300MHz, DMSO-d6) δ 8.60 (d, J = 8.1 Hz, 466 1H), 8.00 (s, 1H), 7.91 (d, J =1.5 Hz, 1H), 7.78 (d, J = 2.2 Hz, 2H), 7.45-7.37 (m, 2H), 7.37-7.29 (m,2H), 6.87 (d, J = 1.8 Hz, 1H), 4.96 (q, J = 7.7 Hz, 2H), 4.80-4.31 (m,5H), 3.84 (s, 3H), 3.70-3.54 (m, 1H), 1.94-1.70 (m, 3H). 152 1 ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 8.76 (br. s., 1H), 466 8.01 (s, 1H), , 7.96 (s,1H), 7.82 (s, 1H), 7.79 (s, 1H), 7.39 (br. s., 4H), 6.94 (s, 1H),5.03-5.00 (m, 1H), 4.98-4.10 (m, 4H), 3.84 (s, 3H), 3.30 (s, 3H), 1.42(d, 3H, J = 6.8 Hz) 153 1 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.69 (t, 1H, J= 6.0 466 Hz), 7.99 (s, 1H), 7.91 (d, 1H, J = 1.2 Hz), 7.78 (d, 2H, J =2.4 Hz), 7.52 (d, 2H, J = 8.8 Hz), 7.23 (d, 2H, J = 8.4 Hz), 6.87 (d,1H, J = 1.2 Hz), 4.69-4.19 (m, 6H), 3.83 (s, 3H), 3.66-3.62 (m, 1H) 1542 ¹H NMR (400 MHz, DMSO-d6) δ 8.53 (t, J = 6.0 Hz, 1H), 467 8.49 (s,1H), 8.30 (d, J = 1.7 Hz, 1H), 8.00 (s, 1H), 7.91 (dd, J = 7.9, 1.5 Hz,1H), 7.84 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.20 (d, J = 1.7 Hz, 1H),7.19-7.09 (m, 4H), 4.87 (br.s, 1H), 4.39 (m, 4H), 4.28 (d, J = 5.8 Hz,2H), 4.00 (br.s, 1H), 2.26 (s, 3H), 1.60 (s, 3H). 155 2 ¹H-NMR (400 MHz,CD₃OD) δ ppm 8.08 (s, 1H), 7.85 (s, 467 1H), 7.57-7.54 (m, 2H),7.23-7.11 (m, 5H), 6.91 (d, 1H, J = 8.0 Hz), 5.03 (br.s, 1H), 4.70(br.s, 1H), 4.56 (br.s, 1H), 4.39 (s, 2H), 4.24 (br.s, 1H), 3.77 (s,2H), 2.29 (s, 3H), 1.72 (s, 3H) 156 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm10.61 (s, 1H), 8.13 467 (d, 1H, J = 1.2 Hz), 7.82-7.77 (m, 5H), 7.68 (d,2H, J = 8.4 Hz), 7.06 (d, 1H, J = 1.2 Hz), 6.96 (d, 2H, J = 8.4 Hz),4.80-4.70 (m, 2H), 4.40-4.30 (m, 2H), 3.84-3.80 (m, 1H), 1.29 (s, 9H)157 2 ¹H NMR (400 MHz, DMSO-d6) δ 8.60 (t, J = 5.9 Hz, 1H), 468 8.14 (d,J = 1.7 Hz, 1H), 7.81 (s, 1H), 7.72-7.62 (m, 2H), 7.34-7.25 (m, 2H),7.21-7.09 (m, 4H), 7.06 (d, J = 1.7 Hz, 1H), 4.81-4.60 (m, 3H),4.42-4.18 (m, 4H), 3.69- 3.56 (m, 1H), 3.53 (d, J = 5.7 Hz, 2H), 2.27(s, 3H), 0.87- 0.80 (m, 2H), 0.73 (t, J = 3.0 Hz, 2H). 158 3 ¹H-NMR (400MHz, CDCl₃) δ ppm 7.89 (s, 1H), 7.84 (s, 468 1H), 7.53-7.48 (m, 4H),7.19-7.09 (m, 4H), 6.87 (s, 1H), 5.96 (br.s, 1H), 4.70 (t, 2H, J = 8.8Hz), 4.39 (d, 2H, J = 5.2 Hz), 3.49-3.47 (m, 1H), 2.53-2.49 (m, 2H),2.37-2.30 (m, 3H), 2.28 (s, 3H), 2.00-1.97 (m, 2H) 159 2 ¹H NMR (400MHz, DMSO-d₆) δ 8.59 (t, J = 5.9 Hz, 1H), 468 8.12 (d, J = 1.7 Hz, 1H),7.28-7.09 (m, 8H), 7.05 (d, J = 1.7 Hz, 1H), 4.74 (s, 1H), 4.65 (s, 2H),3.61 (ddd, J = 14.4, 8.8, 5.7 Hz, 1H), 2.98 (s, 2H), 2.27 (s, 3H), 1.41(s, 6H) 160 2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (t, J = 5.9 Hz, 1H), 4688.05 (d, J = 1.7 Hz, 1H), 7.80 (s, 1H), 7.61 (d, J = 1.9 Hz, 1H),7.60-7.46 (m, 1H), 7.20-7.09 (m, 4H), 7.00 (d, J = 1.7 Hz, 1H),6.80-6.66 (m, 1H), 4.74 (s, 1H), 4.65 (s, 1H), 3.62 (ddd, J = 14.4, 8.7,5.8 Hz, 1H), 3.02 (s, 2H), 2.27 (s, 3H), 1.41 (s, 6H) 161 1 ¹H-NMR (400MHz, DMSO-d₆) δ ppm 8.61 (d, 1H, J = 468 8.0 Hz), 7.97 (s, 1H), 7.88 (s,1H), 7.76 (d, 2H, J = 4.4 Hz), 7.39-7.35 (m, 2H), 7.30-7.27 (m, 1H),6.84 (s, 1H), 4.97-4.91 (m, 1H), 3.81 (s, 3H), 3.66-3.59 (m, 1H), 1.73-1.61 (m, 2H), 0.84 (t, 3H, J = 7.2 Hz) 162 2 ¹H-NMR (400 MHz, DMSO-d₆) δppm 8.64 (t, 1H, J = 5.6 469 Hz), 8.29 (d, 1H, J = 1.2 Hz), 7.88-7.85(m, 3H), 7.42 (d, 2H, J = 8.4 Hz), 7.20-7.13 (m, 5H), 4.83-4.60 (m, 2H),4.42-4.15 (m, 4H), 3.68-3.58 (m, 1H), 2.97 (s, 6H), 2.28 (s, 3H) 163 2¹H NMR (300 MHz, DMSO-d₆) δ 8.53 (t, J = 5.8 Hz, 1H), 469 7.79 (d, J =1.6 Hz, 1H), 7.72 (s, 1H), 7.64 (s, 1H), 7.39- 7.17 (m, 1H), 7.11 (t, J= 8.9 Hz, 1H), 6.71 (d, J = 1.7 Hz, 1H), 4.64 (s, 2H), 4.31 (d, J = 5.7Hz, 2H), 3.92 (s, 3H), 3.54 (s, 2H), 1.54 (s, 3H) 164 3 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.59 (br.s, 1H), 470 8.19 (s, 1H), 7.81-7.79 (m, 3H),7.58 (d, 2H, J = 8.0 Hz), 7.16-7.11 (m, 5H), 6.32 (s, 1H), 4.76 (d, 2H,J = 6.4 Hz), 4.68 (d, 2H, J = 6.0 Hz), 4.26 (br.s, 2H), 2.26 (s, 3H) 1652 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.63 (t, 1H, J = 5.6 470 Hz), 8.15 (d,1H, J = 1.6 Hz), 7.83 (s, 1H), 7.70 (d, 2H, J = 8.4 Hz), 7.17 (d, 2H, J= 8.4 Hz), 7.14 (d, 2H, J = 8.4 Hz), 7.07 (d, J = 1.6 Hz, 1H), 6.98 (d,2H, J = 8.4 Hz), 4.81- 4.60 (m, 2H), 4.42-4.15 (m, 4H), 3.66-3.59 (m,1H), 2.28 (s, 3H), 1.31 (s, 9H) 166 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm8.53 (t, J = 5.6 Hz, 470 1H), 8.90 (s, 1H), 7.81 (s, 1H), 7.67 (d, 2H, J= 8.8 Hz), 7.14 (d, 2H, J = 8.4 Hz), 7.11 (d, 2H, J = 8.4 Hz), 6.99 (s,1H), 6.91 (d, 2H, J = 8.8 Hz), 4.84 (br. s., 1H), 4.66-4.60 (m, 1H),4.37 (br. s., 2H), 4.28 (d, 2H, J = 5.6 Hz), 3.98 (br. s., 1H), 2.26 (s,3H), 1.60 (s, 3H), 1.26 (d, 6H, J = 6.0 Hz) 167 2 ¹H NMR (400 MHz,DMSO-d6) δ 8.60 (t, J = 5.9 Hz, 1H), 470 8.19 (d, J = 1.6 Hz, 1H), 7.82(d, J = 0.9 Hz, 1H), 7.54- 7.45 (m, 1H), 7.39-7.33 (m, 1H), 7.27 (t, J =7.9 Hz, 1H), 7.20-7.05 (m, 5H), 6.86 (ddd, J = 8.2, 2.1, 1.1 Hz, 1H),4.72 (m, 2H), 4.39-4.17 (m, 4H), 3.63 (m, 1H), 2.27 (s, 3H), 1.32 (s,9H). 168 2 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.88 (s, 1H), 7.85 (d, 470 1H,J = 1.2 Hz), 7.53 (s, 4H), 7.22-7.11 (m, 4H), 6.86 (d, 1H, J = 1.2 Hz),6.29 (br.s, 1H), 4.45 (d, 2H, J = 5.6 Hz), 4.30 (d, 2H, J = 4.0 Hz),2.33 (s, 3H), 1.71 (s, 3H), 1.61 (s, 6H) 169 3 ¹H-NMR (400 MHz, CDCl₃) δppm 7.87 (s, 1H), 7.84 (s, 470 1H), 7.57 (d, 2H, J = 8.4 Hz), 7.47 (d,2H, J = 8.4 Hz), 7.22-7.17 (m, 4H), 6.78 (d, 1H, J = 1.6 Hz), 5.82(br.s, 1H), 4.62 (br.s, 4H), 4.48 (d, 2H, J = 6.0 Hz), 3.55-3.48 (m,1H), 2.36 (s, 3H) 1.93-1.83 (m, 2H), 1.59 (s, 3H), 0.85 (t, 3H, J = 7.6Hz) 170 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.54 (d, 1H, J = 470 8.0 Hz),8.16 (s, 1H), 7.82 (s, 1H), 7.70 (d, 2H, J = 8.0 Hz), 7.46 (d, 2H, J =8.4 Hz), 7.21 (d, 2H, J = 8.0 Hz), 7.14 (d, 2H, J = 7.6 Hz), 7.07 (s,1H), 5.00 (s, 1H), 4.97- 4.91 (m, 1H), 4.75-4.58 (m, 2H), 4.35-4.13 (m,2H), 3.60- 3.59 (m, 1H), 2.27 (s, 3H), 1.43 (s, 6H), 1.36 (d, 3H, J =6.8 Hz) 171 1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.85 (t, J = 6.1 Hz, 1H), 4708.07-7.67 (m, 4H), 7.50-7.12 (m, 3H), 6.94 (d, J = 1.6 Hz, 1H), 4.36 (d,J = 6.0 Hz, 6H), 3.83 (s, 3H), 3.33 (s, 3H) 172 1 ¹H-NMR (400 MHz,CD₃OD) δ ppm 8.08 (s, 1H), 7.96 (s, 470 1H), 7.90 (s, 1H), 7.82 (s, 1H),7.47-7.45 (m, 2H), 7.34 (dd, 1H, J = 8.4, 2.4 Hz), 7.30 (s, 1H), 5.09(br.s, 1H), 4.70 (br.s, 2H), 4.49 (br.s, 2H), 4.14-4.13 (m, 1H), 3.91(s, 3H), 1.49 (d, 3H, J = 7.6 Hz) 173 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm8.00 (d, 1H, J = 471 8.0 Hz), 7.91 (s, 1H), 7.25-7.14 (m, 5H), 6.30(br.s, 1H), 4.39 (s, 2H), 4.21 (d, 2H, J = 2.0 Hz), 3.81-3.73 (m, 3H),2.66-2.52 (m, 2H), 2.31 (s, 3H), 2.16 (d, 3H, J = 15.2 Hz) 174 2 ¹H-NMR(400 MHz, CD₃OD) δ ppm 8.69 (d, 1H, J = 8.0 472 Hz), 8.12 (s, 1H), 7.87(s, 1H), 7.64 (d, 2H, J = 8.0 Hz), 7.39-7.30 (m, 3H), 7.10-7.04 (m, 4H),5.09-5.00 (m, 1H), 4.65-4.48 (m, 4H), 3.81-3.76 (m, 1H), 1.48 (d, 3H, J= 6.8 Hz), 0.81-0.79 (m, 2H), 0.72-0.70 (m, 2H) 175 2 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.63 (t, 1H, J = 6.0 472 Hz), 8.16 (s, 1H), 7.85 (s, 1H),7.72 (d, 2H, J = 8.8 Hz), 7.17 (d, 2H, J = 8.8 Hz), 7.14 (d, 2H, J = 8.8Hz), 7.10 (s, 1H), 6.96 (d, 2H, J = 8.8 Hz), 4.78-4.67 (m, 2H), 4.38-4.22 (m, 4H), 4.13-4.10 (m, 2H), 3.68-3.60 (m, 3H), 3.32 (s, 3H), 2.28(s, 3H) 176 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.64 (t, 1H, J = 5.6 472Hz), 8.08 (s, 1H), 7.94 (d, 1H, J = 1.2 Hz), 7.84 (s, 1H), 7.80 (s, 1H),7.16 (d, 2H, J = 8.4 Hz), 7.13 (d, 2H, J = 8.4 Hz), 6.90 (d, 1H, J = 1.2Hz), 4.79-4.50 (m, 4H), 4.41-4.12 (m, 8H), 3.69-3.56 (m, 1H), 2.28 (s,3H), 1.15 (s, 3H) 177 1 ¹H-NMR (400 MHz, CD₃OD) δ ppm 8.10 (s, 1H), 7.96(s, 472 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.51-7.48 (m, 2H), 7.37- 7.33(m, 2H), 5.51 (s, 1H), 5.14 (br.s, 1H), 4.96-4.94 (m, 3H), 4.58 (br.s,1H), 3.92 (s, 3H) 178 1 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 10.62 (s, 1H),8.41 473 (s, 1H), 8.07 (d, 2H, J = 8.4 Hz), 7.91-7.88 (m, 2H), 7.83-7.78 (m, 4H), 7.32 (s, 1H), 4.85-4.75 (m, 2H), 4.46-4.35 (m, 2H),3.85-3.83 (m, 1H), 3.21 (s, 3H) 179 2 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.89(s, 1H), 7.71 (d, 473 1H, J = 8.4 Hz), 7.18-7.09 (m, 4H), 6.99 (br.s,1H), 6.91 (s, 1H), 6.20-6.02 (m, 1H), 5.26 (d, 1H, J = 8.4 Hz), 4.52(br.s, 1H), 4.42-4.40 (m, 3H), 4.26 (br.s, 1H), 4.15 (br.s, 1H), 3.85(br.s, 1H), 3.70 (br.s, 1H), 2.52-2.40 (m, 4H), 2.32 (s, 3H), 1.72 (s,3H), 1.21-1.18 (m, 3H) 180 2 ¹H-NMR (400 MHz, CD₃OD) δ ppm 8.67 (d, 1H,J = 7.6 474 Hz), 8.03 (s, 1H), 7.82 (s, 1H), 7.38-7.35 (m, 2H), 7.18-7.15 (m, 3H), 7.08-7.03 (m, 2H), 6.84 (d, 2H, J = 8.4 Hz), 5.08-5.03 (m,3H), 4.26 (s, 4H), 3.78-3.72 (m, 1H), 1.48 (d, 3H, J = 7.2 Hz) 181 2¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.59 (d, 1H, J = 474 8.0 Hz), 8.10 (d,1H, J = 1.6 Hz), 7.81 (s, 1H), 7.69 (d, 2H, J = 9.2 Hz), 7.38-7.35 (m,2H), 7.18-7.13 (m, 2H), 7.02 (s, 1H), 6.93 (d, 2H, J = 8.8 Hz),5.02-4.95 (m, 1H), 4.82- 4.56 (m, 3H), 4.42-4.13 (m, 2H), 3.63-3.61 (m,1H), 1.38 (d, 3H, J = 7.2 Hz), 1.28 (d, 6H, J = 6.0 Hz) 182 2 ¹H-NMR(400 MHz, CD₃OD) δ 8.29 (s, 1H), 7.93 (s, 1H), 474 7.70 (br.s, 1H),7.56-7.54 (m, 1H), 7.50-7.48 (m, 1H), 7.36-7.35 (m, 3H), 7.08-7.04 (m,3H), 5.11-5.02 (m, 4H), 4.64 (br.s, 1H), 3.81 (s, 1H), 1.54-1.48 (m,6H), 1.34 (s, 3H) 183 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.64 (t, 1H, J =5.6 474 Hz), 8.11 (s, 1H), 7.80 (s, 1H), 7.67 (d, 2H, J = 8.4 Hz),7.32-7.29 (m, 2H), 7.14 (t, 2H, J = 8.8 Hz), 7.03 (s, 1H), 6.96 (d, 2H,J = 8.4 Hz), 4.74-4.65 (m, 2H), 4.30 (d, 2H, J = 5.6 Hz), 4.30-4.20 (m,2H), 3.65-3.55 (m, 1H), 1.29 (s, 9H) 184 3 ¹H-NMR (400 MHz, CD₃OD) δ ppm7.93-7.89 (m, 2H), 474 7.75 (s, 1H), 7.63-7.58 (m, 1H), 7.20-7.13 (m,4H), 7.06- 7.05 (m, 1H), 6.99 (s, 1H), 4.38 (s, 2H), 3.70-3.67 (m, 1H),2.31 (s, 3H), 1.61 (s, 6H) 185 2 ¹H NMR (400 MHz, DMSO-d6) δ 8.58 (t, J= 5.9 Hz, 1H), 474 7.82-7.75 (m, 2H), 7.19-7.08 (m, 4H), 6.79 (d, J =1.7 Hz, 1H), 6.19 (d, J = 3.3 Hz, 1H), 4.63 (m, 2H), 4.27 (m, 4H), 3.79(m, 2H), 3.60 (m, 1H), 2.75 (s, 6H), 2.26 (s, 3H) - one set of protonsmostly obscured by DMSO peak. 186 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.62(t, 1H, J = 5.6 474 Hz), 7.96 (s, 2H), 7.80 (s, 2H), 7.17 (d, 2H, J =8.0 Hz), 7.14 (d, 2H, J = 8.0 Hz), 6.92 (s, 1H), 4.70-4.62 (m, 2H), 4.34(br. s., 1H), 4.29 (d, 2H, J = 5.2 Hz), 4.21 (br. s., 1H), 4.11 (s, 2H),3.66-3.59 (m, 1H), 3.19 (s, 3H), 2.28 (s, 3H), 1.09 (s, 6H). 187 2¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.53 (d, 1H, J = 474 8.0 Hz), 8.00 (s,1H), 7.94 (d, 1H, J = 2.0 Hz), 7.80 (s, 1H), 7.79 (s, 1H), 7.20 (d, 2H,J = 8.0 Hz), 7.13 (d, 2H, J = 8.0 Hz), 6.90 (s, 1H), 4.97-4.91 (m, 1H),4.73 (s, 1H), 4.73-3.99 (m, 4H), 3.99 (s, 2H), 3.64-3.58 (m, 1H), 2.27(s, 3H), 1.35 (d, 3H, J = 6.8 Hz), 1.08 (s, 6H) 188 2 ¹H-NMR (400 MHz,CD₃OD) δ ppm 7.90 (s, 1H), 7.85 (s, 475 1H), 7.25-7.12 (m, 5H), 6.24(br.s, 1H), 4.38 (s, 2H), 4.18- 4.11 (m, 4H), 3.77-3.68 (m, 3H), 2.52(br.s, 2H), 2.31 (s, 3H), 1.28 (t, 3H, J = 7.2 Hz) 189 2 ¹H-NMR (400MHz, CDCl₃) δ ppm 7.77 (s, 1H), 7.65 (s, 475 1H), 7.18-7.16 (m, 1H),7.09-7.03 (m, 4H), 6.87 (s, 1H), 6.04 (br.s, 1H), 5.20 (d, 1H, J = 9.2Hz), 4.77 (d, 1H, J = 10.0 Hz), 4.48 (d, 1H, J = 9.6 Hz), 4.34-4.32 (m,3H), 4.06 (br.s, 2H), 3.68 (s, 3H), 3.64 (d, 2H, J = 6.0 Hz), 2.40(br.s, 2H), 2.24 (s, 3H), 1.65 (s, 3H) 190 1 ¹H-NMR (400 MHz, DMSO-d₆) δppm 8.65 (t, 1H, J = 5.6 476 Hz), 8.40 (d, 1H, J = 1.2 Hz), 8.09 (d, 2H,J = 8.8 Hz), 7.90 (d, 2H, J = 8.4 Hz), 7.87 (s, 1H), 7.29 (d, 1H, J =0.4 Hz), 7.17 (d, 2H, J = 8.0 Hz), 7.14 (d, 2H, J = 8.0 Hz), 4.87-4.61(m, 2H), 4.42-4.16 (m, 4H), 3.68-3.59 (m, 1H), 3.24 (s, 3H), 2.28 (s,3H) 191 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.58 (d, 1H, J = 477 8.0 Hz),8.22 (s, 1H), 8.05 (s, 1H), 7.89 (d, 1H, J = 9.2 Hz), 7.80 (s, 1H), 7.39(d, 2H, J = 8.4 Hz), 7.32 (d, 2H, J = 8.0 Hz), 6.99 (s, 1H), 6.44 (d,1H, J = 9.6 Hz), 4.76-4.52 (m, 3H), 4.50-4.00 (m, 2H), 3.66-3.63 (m,1H), 3.46 (s, 3H), 1.70-1.66 (m, 2H), 0.85-0.82 (m, 3H) 192 2 ¹H-NMR(400 MHz, CD₃OD) δ ppm 8.71 (d, 1H, J = 7.2 478 Hz), 8.07 (s, 1H), 8.01(br.s, 1H), 7.89 (s, 1H), 7.85 (br.s, 1H), 7.39-7.35 (m, 2H), 7.28(br.s, 1H), 7.06 (t, 2H, J = 7.2 Hz), 5.09-5.07 (m, 1H), 4.94 (br.s,1H), 4.67-4.49 (m, 3H), 4.11 (s, 2H), 3.80-3.78 (m, 1H), 1.48 (d, 3H, J= 7.2 Hz), 1.19 (s, 6H) 193 2 ¹H-NMR (400 MHz, CD₃OD) δ ppm 7.92 (s,1H), 7.78 (s, 478 2H), 7.72 (s, 1H), 7.24 (t, 1H, J = 8.0 Hz), 6.98-6.91(m, 2H), 6.87 (s, 1H), 4.43 (s, 2H), 4.10 (s, 2H), 3.71-3.65 (m, 1H),2.33 (s, 3H), 1.19 (s, 6H) 194 3 ¹H-NMR (400 MHz, CD₃OD) δ ppm 8.71 (d,1H, J = 7.6 478 Hz), 8.15 (s, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 7.86 (s,1H), 7.39-7.35 (m, 3H), 7.06 (t, 2H, J = 8.4 Hz), 5.13-5.04 (m, 2H),4.68-4.62 (m, 2H), 4.51 (br.s, 1H), 3.82-3.79 (m, 1H), 3.76 (s, 2H),1.56 (s, 6H), 1.48 (d, 3H, J = 6.8 Hz) 195 3 ¹H-NMR (400 MHz, CD₃OD) δppm 8.69 (d, 1H, J = 7.2 478 Hz), 8.05 (s, 1H), 7.99 (br.s, 1H), 7.87(s, 1H), 7.84 (s, 1H), 7.38-7.35 (m, 2H), 7.24 (br.s, 1H), 7.06 (t, 2H,J = 8.8 Hz), 5.09-5.05 (m, 1H), 5.04-4.89 (m, 2H), 4.81-4.40 (m, 2H),4.21-4.16 (m, 1H), 4.10-4.04 (m, 1H), 3.86 (br.s, 1H), 3.79-3.76 (m,1H), 1.49-1.47 (m, 5H), 1.03-0.98 (m, 3H) 196 3 ¹H-NMR (400 MHz, CDCl₃)δ ppm 7.84 (br.s, 1H), 7.74 478 (s, 1H), 7.65 (s, 1H), 7.60 (s, 1H),6.99-6.94 (m, 2H), 6.86 (s, 1H), 6.50 (s, 1H), 6.37 (s, 1H), 5.04 (br.s,2H), 4.70 (br.s, 3H), 4.26-4.25 (m, 1H), 4.12-4.10 (m, 1H), 3.55 (br.s,1H), 1.49 (d, 3H, J = 6.8 Hz), 1.44 (d, 3H, J = 6.8 Hz), 1.11 (d, 3H, J= 6.8 Hz) 197 2 ¹H-NMR (400 MHz, CD₃OD) δ ppm 7.95 (s, 1H), 7.74- 4787.73 (m, 2H), 7.68 (s, 1H), 7.33-7.28 (m, 4H), 6.81 (s, 1H), 4.81-4.77(m, 2H), 4.57-4.50 (m, 4H), 3.70-3.66 (m, 1H), 1.82-1.78 (m, 2H), 1.50(d, 6H, J = 6.8 Hz), 0.92 (t, 3H, J = 7.6 Hz) 198 2 ¹H-NMR (400 MHz,CDCl₃) δ ppm 7.77 (br.s, 1H), 7.73 478 (s, 1H), 7.65 (br.s, 1H), 7.60(s, 1H), 7.36-7.12 (m, 5H), 6.91 (s, 1H), 5.16 (br.s, 1H), 4.96 (br.s,1H), 4.83-4.74 (m, 1H), 4.51-4.45 (m, 2H), 4.35 (br.s, 1H), 1.64 (d, 3H,J = 19.6 Hz), 1.48 (d, 6H, J = 6.8 Hz), 1.40 (d, 3H, J = 5.6 Hz) 199 2¹H-NMR (400 MHz, CD₃OD) δ ppm 8.65 (d, 1H, J = 7.6 479 Hz), 7.87 (s,1H), 7.83 (s, 1H), 7.37-7.34 (m, 2H), 7.07- 7.03 (m, 3H), 6.22 (br.s,1H), 5.07-5.04 (m, 1H), 4.58 (br.s, 4H), 4.10 (s, 2H), 3.73 (br.s, 1H),3.72 (s, 3H), 3.69- 3.68 (m, 2H), 2.51 (br.s, 2H), 1.47 (d, 2H, J = 6.8Hz) 200 2 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.87 (s, 1H), 7.75 (s, 479 1H),7.25 (br.s, 2H), 7.03 (t, 2H, J = 8.4 Hz), 6.96 (s, 1H), 6.14 (br.s,1H), 5.29 (d, 1H, J = 7.6 Hz), 4.88 (br.s, 1H), 4.59-4.42 (m, 4H), 4.16(br.s, 2H), 3.77 (s, 3H), 3.72 (br.s, 2H), 2.49 (br.s, 2H), 1.75 (s, 3H)201 2 ¹H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 8.1 Hz, 480 1H), 7.90 (s,1H), 7.83-7.70 (m, 2H), 7.42-7.34 (m, 2H), 7.31 (d, J = 8.4 Hz, 2H),6.74 (s, 1H), 4.99-4.90 (m, 1H), 4.78-4.00 (m, 6H), 3.75 (s, 3H), 3.60(td, J = 8.5, 4.2 Hz, 1H), 2.29 (s, 3H), 1.91-1.72 (m, 2H) - one peakpartially obscured by water signal. 202 2 ¹H NMR (400 MHz, DMSO-d6) δ8.41 (d, J = 8.0 Hz, 480 1H), 7.99 (s, 1H), 7.90 (d, J = 1.6 Hz, 1H),7.78 (d, J = 7.4 Hz, 2H), 7.42-7.35 (m, 2H), 7.32 (d, J = 8.5 Hz, 2H),6.84 (d, J = 1.7 Hz, 1H), 5.00-4.89 (m, 1H), 4.76 (br.s, 1H), 4.57 (t, J= 4.9 Hz, 1H), 4.30 (br.s, 2H), 3.99 (br.s, 1H), 3.83 (s, 3H), 1.97-1.83(m, 1H), 1.85-1.72 (m, 1H), 1.57 (s, 3H) - one peak partially obscuredby water signal. 203 1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (d, J = 8.5 Hz,1H), 480 7.99 (s, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.79 (d, J = 12.8 Hz,2H), 7.37 (s, 4H), 6.92 (s, 1H), 5.00-3.90 (m, 5H), 3.83 (s, 3H), 3.28(s, 3H), 1.76 (ddt, J = 40.6, 13.7, 6.7 Hz, 2H), 0.86 (t, J = 7.3 Hz,3H) 204 2 ¹H-NMR (400 MHz, CD₃OD) δ ppm 7.92 (s, 1H), 7.78 (s, 480 2H),7.72 (s, 1H), 7.35-7.29 (m, 4H), 6.87 (s, 1H), 4.41 (s, 2H), 4.10 (s,2H), 3.68-3.67 (m, 1H), 1.19 (s, 6H) 205 2 ¹H-NMR (400 MHz, CD₃OD) δ ppm7.93 (s, 1H), 7.78 (s, 480 1H), 7.75 (s, 1H), 7.34-7.28 (m, 4H), 6.85(s, 1H), 4.23 (t, 2H, J = 5.2 Hz), 3.89 (t, 2H, J = 5.2 Hz), 3.69-3.65(m, 1H), 1.81 (t, 2H, J = 7.6 Hz), 0.92 (t, 3H, J = 7.6 Hz) 206 3 ¹H-NMR(400 MHz, CDCl₃) δ ppm 7.79 (s, 1H), 7.74 (s, 481 1H), 7.59 (d, 2H, J =8.8 Hz), 7.51 (d, 2H, J = 8.8 Hz), 7.14-7.09 (m, 4H), 6.67 (s, 1H), 5.73(br.s, 1H), 4.40 (d, 2H, J = 5.6 Hz), 3.83 (t, 2H, J = 6.8 Hz),3.49-3.43 (m, 1H), 3.10-3.05 (m, 1H), 2.57 (t, 2H, J = 8.0 Hz), 2.23 (s,3H), 2.14-2.12 (m, 2H) 207 2 ¹H NMR (400 MHz, DMSO-d6) δ 8.59 (t, J =5.9 Hz, 1H), 481 7.83 (d, J = 1.6 Hz, 1H), 7.80 (s, 1H), 7.19-7.06 (m,4H), 6.84 (d, J = 1.7 Hz, 1H), 6.25 (m, 1H), 4.76-4.54 (m, 2H),4.40-4.15 (m, 4H), 3.87-3.77 (m, 2H), 3.61 (ddd, J = 14.3, 8.7, 5.7 Hz,1H), 2.92 (s, 3H), 2.56 (br.s, 2H), 2.27 (s, 3H). 208 2 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.61 (t, 1H, J = 5.8 482 Hz), 8.25 (d, 1H, J = 1.5 Hz),7.92 (d, 2H, J = 8.7 Hz), 7.84 (s, 1H), 7.37 (d, 2H, J = 8.3 Hz),7.21-7.08 (m, 5H), 4.76-4.67 (m, 2H), 4.40-4.14 (m, 4H), 3.69-3.55 (m,1H), 2.27 (s, 3H) 209 2 ¹H-NMR (400 MHz, CD₃OD) δ ppm 7.92 (s, 1H), 7.78(s, 482 2H), 7.72 (s, 1H), 7.44-7.40 (m, 1H), 6.98-6.92 (m, 2H), 6.86(d, 1H, J = 1.2 Hz), 4.45 (s, 2H), 4.10 (s, 2H), 3.71- 3.63 (m, 1H),1.19 (s, 6H) 210 3 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.78 (s, 1H), 7.77 (s,482 1H), 7.50 (s, 4H), 7.14-7.08 (m, 4H), 6.74 (s, 1H), 5.88 (br.s, 1H),4.59 (br.s, 1H), 4.40 (d, 2H, J = 5.2 Hz), 3.49- 3.48 (m, 1H), 2.27 (s,3H), 1.46 (s, 3H), 1.23-1.18 (m, 1H), 0.50-0.37 (m, 4H) 211 3 ¹H-NMR(400 MHz, CD₃OD) δ ppm 7.93 (s, 1H), 7.74 (s, 482 1H), 7.64 (d, 2H, J =8.4 Hz), 7.50 (d, 2H, J = 8.4 Hz), 7.20-7.13 (m, 4H), 7.01 (s, 1H), 4.38(s, 2H), 3.69-3.68 (m, 1H), 2.31 (s, 3H), 2.02-1.84 (m, 8H) 212 2 ¹H NMR(400 MHz, DMSO-d6) δ 8.84-8.75 (m, 1H), 483 8.50 (s, 1H), 8.34 (d, J =1.9 Hz, 1H), 8.01 (s, 1H), 7.97- 7.91 (m, 1H), 7.87 (d, J = 1.4 Hz, 1H),7.65 (d, J = 7.7 Hz, 1H), 7.30 (d, J = 1.9 Hz, 1H), 7.22-7.06 (m, 3H),4.89 (d, J = 9.5 Hz, 1H), 4.72 (d, J = 10.1 Hz, 1H), 4.40 (m, 3H), 4.30(m, 3H), 2.26 (s, 3H). 213 3 ¹H-NMR (400 MHz, CD₃OD) δ ppm 7.95 (s, 1H),7.74 (s, 484 1H), 7.69 (d, 2H, J = 8.4 Hz), 7.53 (d, 2H, J = 8.4 Hz),7.20-7.13 (m, 4H), 7.03 (s, 1H), 4.38 (s, 2H), 4.18-4.11 (m, 1H),3.96-3.88 (m, 2H), 2.46-2.38 (m, 1H), 2.31 (s, 3H) 214 2 ¹H-NMR (400MHz, CDCl₃) δ ppm 7.93 (s, 1H), 7.86 (s, 484 1H), 7.46 (d, 2H, J = 8.4Hz), 7.18-7.12 (m, 4H), 7.04 (d, 2H, J = 8.4 Hz), 6.96 (s, 1H), 6.62(br.s, 1H), 4.44-4.38 (m, 4H), 2.32 (s, 3H), 1.72 (s, 3H), 1.38 (s, 9H)215 2 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.86 (s, 1H), 7.78 (d, 484 1H, J =1.6 Hz), 7.48 (d, 2H, J = 8.8 Hz), 7.23 (d, 2H, J = 8.4 Hz), 7.18 (d,2H, J = 8.0 Hz), 7.03 (d, 2H, J = 8.4 Hz), 6.71 (d, 1H, J = 1.2 Hz),5.72 (d, 1H, J = 7.6 Hz), 5.20- 5.12 (m, 1H), 4.64-4.59 (m, 4H),3.50-3.43 (m, 1H), 2.36 (s, 3H), 1.54 (d, 3H, J = 6.8 Hz), 1.38 (s, 9H)216 3 ¹H-NMR (400 MHz, CD₃OD) δ ppm 8.87 (s, 1H), 7.73 (s, 484 1H), 7.58(d, 2H, J = 8.4 Hz), 7.20-7.13 (m, 4H), 7.00 (d, 2H, J = 8.4 Hz), 6.96(s, 1H), 4.38 (s, 2H), 3.71-3.66 (m, 1H), 2.30 (s, 3H), 1.73-1.67 (m,2H), 1.28 (s, 6H), 2.31 (t, 3H, J = 7.2 Hz) 217 2 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.59 (t, 1H, J = 5.6 484 Hz), 8.11 (s, 1H), 7.80 (s, 1H),7.67 (d, 2H, J = 8.4 Hz), 7.19-7.14 (m, 4H), 7.04 (s, 1H), 6.96 (d, 2H,J = 8.8 Hz), 4.73-4.64 (m, 2H), 4.28-4.27 (m, 4H), 3.65-3.55 (m, 1H),2.57-2.55 (m, 2H), 1.29 (s, 9H), 1.14 (t, 3H, J = 7.6 Hz) 218 2 ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 8.56 (d, 1H, J = 485 7.6 Hz), 8.25 (d, 1H, J =0.8 Hz), 7.85-7.83 (m, 3H), 7.40 (d, 2H, J = 7.6 Hz), 7.33-7.31 (m, 4H),7.25-7.21 (m, 1H), 7.16 (s, 1H), 4.95-4.90 (m, 2H), 4.77-4.58 (m, 2H),4.35- 4.12 (m, 2H), 3.75-3.70 (m, 1H), 3.59-3.56 (m, 2H), 2.96 (br. s.,6H) 219 2 ¹H-NMR (500 MHz, DMSO-d₆) δ ppm 8.57 (d, 1H, J = 485 8.0 Hz),8.26 (s, 1H), 7.86-7.84 (m, 3H), 7.41 (d, 2H, J = 7.5 Hz), 7.33-7.30 (m,4H), 7.26-7.22 (m, 1H), 7.17 (s, 1H), 4.94-4.90 (m, 2H), 4.77-4.50 (m,2H), 4.45-4.36 (m, 2H), 3.75-3.69 (m, 1H), 3.61-3.32 (m, 2H), 2.97 (br.s., 6H) 220 3 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.93 (s, 1H), 7.73 (s, 4861H), 7.69-7.64 (m, 2H), 7.38-7.34 (m, 2H), 7.08-7.02 (m, 3H), 5.07(br.s, 2H), 5.05 (br.s, 1H), 4.58 (br.s, 2H), 3.69- 3.66 (m, 1H),2.54-2.51 (m, 2H), 2.40-2.33 (m, 2H), 2.03- 2.00 (m, 1H), 1.75-1.70 (m,1H), 1.47 (d, 3H, J = 7.2 Hz) 221 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.62(t, 1H, J = 5.6 486 Hz), 8.11 (d, 1H, J = 1.6 Hz), 7.81 (s, 1H), 7.70(d, 2H, J = 8.4 Hz), 7.16 (d, 2H, J = 7.6 Hz), 7.12 (d, 2H, J = 8.0 Hz),7.03 (d, 1H, J = 1.2 Hz), 6.94 (d, 2H, J = 8.8 Hz), 4.83- 4.64 (m, 3H),4.42-4.11 (m, 4H), 3.72 (s, 2H), 3.66-3.56 (m, 1H), 2.27 (s, 3H), 1.20(s, 6H) 222 2 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.89 (s, 1H), 7.85 (d, 4861H, J = 1.6 Hz), 7.58 (d, 2H, J = 8.8 Hz), 7.53 (d, 2H, J = 8.8 Hz),7.21 (d, 2H, J = 8.4 Hz), 7.18 (d, 2H, J = 8.4 Hz), 6.81-6.79 (m, 2H),5.05-4.48 (m, 4H), 5.49 (d, 2H, J = 5.6 Hz), 3.48 (s, 3H), 2.37 (s, 3H),1.63 (s, 6H) 223 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.67-8.54 (m, 1H),487 8.00 (s, 1H), 7.93 (d, 1H, J = 1.2 Hz), 7.80 (s, 1H), 7.78 (s, 1H),7.17-7.14 (m, 4H), 6.90 (d, 1H, J = 1.2 Hz), 4.80- 4.49 (m, 2H),4.48-4.37 (m, 1H), 4.28-4.25 (m, 2H), 4.23- 4.13 (m, 1H), 4.09-4.06 (m,2H), 3.72-3.68 (m, 2H), 3.65- 3.55 (m, 1H), 3.41-3.36 (m, 2H), 2.77-2.70(m, 1H), 2.67- 2.56 (m, 2H), 2.39-2.33 (m, 1H), 2.27 (s, 3H) 224 2 ¹HNMR (400 MHz, DMSO-d₆) δ 8.58 (t, J = 5.9 Hz, 1H), 487 7.84-7.75 (m,2H), 7.20-7.08 (m, 4H), 6.79 (d, J = 1.7 Hz, 1H), 6.21 (t, J = 3.5 Hz,1H), 4.64 (m, 2H), 4.42-4.05 (m, 8H), 3.73 (t, J = 5.6 Hz, 2H), 3.60 (m,1H), 2.26 (s, 3H), 1.21 (s, 9H) 225 2 ¹H NMR (300 MHz, DMSO-d6) δ 8.44(d, J = 7.8 Hz, 488 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.83 (s, 1H), 7.70(d, J = 8.3 Hz, 2H), 7.51-7.43 (m, 2H), 7.41-7.32 (m, 2H), 7.20- 7.10(m, 2H), 7.05 (d, J = 1.7 Hz, 1H), 4.99 (m, 2H), 4.84 (br.s, 1H),4.43-4.31 (m, 2H), 4.00 (br.s, 1H), 1.60 (s, 3H), 1.44 (s, 6H), 1.39 (d,J = 7.0 Hz, 3H). 226 3 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.96 (s, 1H), 7.88(s, 488 1H), 7.29 (s, 1H), 7.22-7.09 (m, 6H), 6.97 (s, 1H), 6.33 (br.s,1H), 4.83 (br.s, 1H), 4.45 (br.s, 2H), 3.62 (br.s, 1H), 2.32 (s, 3H),1.39 (s, 9H) 227 3 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.92 (s, 1H), 7.79 (s,488 1H), 7.26-7.20 (m, 6H), 7.18-7.13 (m, 1H), 6.75 (s, 1H), 5.87 (br.s,1H), 4.68 (br.s, 1H), 4.49 (d, 2H, J = 5.6 Hz), 3.58-3.52 (m, 1H), 2.37(s, 3H), 1.43 (s, 9H) 228 3 ¹H-NMR (400 MHz, CD₃OD) δ ppm 7.91 (s, 1H),7.72 (s, 488 1H), 7.62 (d, 2H, J = 7.6 Hz), 7.45 (d, 2H, J = 8.4 Hz),7.38-7.34 (m, 2H), 7.05 (t, 2H, J = 8.4 Hz), 6.99 (s, 1H), 5.06-5.05 (m,1H), 4.90 (br.s, 2H), 4.44 (br.s, 2H), 3.69- 3.66 (m, 1H), 1.85-1.79 (m,2H), 1.52 (s, 3H), 1.47 (d, 3H, J = 6.8 Hz), 0.79 (t, 3H, J = 7.6 Hz)229 2 ¹H NMR (400 MHz, DMSO-d6) δ 8.58 (t, J = 5.8 Hz, 1H), 4897.86-7.73 (m, 2H), 7.20-7.08 (m, 4H), 6.79 (d, J = 1.7 Hz, 1H), 6.19(br.s, 1H), 4.87-4.74 (m, 1H), 4.71-4.54 (m, 2H), 4.37-4.15 (m, 4H),4.00 (br.s, 2H), 3.65-3.52 (m, 3H), 2.43 (br.s, 2H), 2.27 (s, 3H), 1.19(d, J = 6.2 Hz, 6H). 230 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.58 (d, 1H,J = 490 7.2 Hz), 8.06 (s, 1H), 7.92 (d, 1H, J = 1.6 Hz), 7.81 (s, 1H),7.78 (s, 2H), 7.37-7.34 (m, 2H), 7.17-7.12 (m, 2H), 6.88 (s, 1H),4.99-4.95 (m, 1H), 4.73-4.59 (m, 4H), 4.32- 4.22 (m, 6H), 3.63-3.59 (m,1H), 1.36 (d, 3H, J = 7.2 Hz), 1.14 (s, 3H) 231 2 ¹H NMR (400 MHz,DMSO-d₆) δ 8.77 (t, J = 6.3 Hz, 1H), 490 8.15-7.66 (m, 4H), 7.30-7.06(m, 4H), 6.96 (d, J = 1.7 Hz, 1H), 5.02-4.07 (m, 7H), 3.99 (s, 2H), 2.26(s, 3H), 1.07 (s, 6H) 232 1 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.56 (t, J =6.0 Hz, 490 1H), 8.41 (s, 1H), 8.08 (d, 2H, J = 8.4 Hz), 7.89 (d, 2H, J= 8.4 Hz), 7.87 (s, 1H), 7.28 (s, 1H), 7.17-7.09 (m, 4H), 4.90 (br. s.,1H), 4.41 (br. s., 2H), 4.29 (d, 2H, J = 5.6 Hz), 4.03 (br. s., 1H),3.22 (s, 3H), 2.26 (s, 3H), 1.61 (s, 3H) 233 2 ¹H-NMR (400 MHz, DMSO-d₆)δ ppm 8.66 (t, 1H, J = 6.0 490 Hz), 8.11 (d, 1H, J = 1.2 Hz), 7.80 (s,1H), 7.67 (d, 2H, J = 8.4 Hz), 7.37 (d, 2H, J = 8.0 Hz), 7.28 (d, 2H, J= 8.4 Hz), 7.03 (d, 1H, J = 1.2 Hz), 6.96 (d, 2H, J = 8.4 Hz), 4.73-4.64 (m, 2H), 4.30 (d, 2H, J = 5.6 Hz), 4.30-4.20 (m, 2H), 3.64-3.61 (m,1H), 1.29 (s, 9H) 234 2 ¹H NMR (300 MHz, DMSO-d6) δ 8.41 (d, J = 8.2 Hz,490 1H), 7.81 (m, 3H), 7.44-7.29 (m, 4H), 6.74 (d, J = 1.7 Hz, 1H),4.92-4.57 (m, 2H), 4.34 (s, 2H), 4.07 (t, J = 7.2 Hz, 3H), 3.03 (t, J =7.3 Hz, 2H), 2.61 (q, J = 7.3 Hz, 2H), 1.73 (mbr., 2H), 1.59 (s, 3H),0.87 (t, J = 7.2 Hz, 3H). 235 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.77 (t,1H, J = 6.0 491 Hz), 7.83 (d, 2H, J = 1.6 Hz), 7.81 (s, 1H), 7.15 (d,2H, J = 8.0 Hz), 7.11 (d, 2H, J = 8.0 Hz), 6.87 (d, 1H, J = 1.6 Hz),6.21 (br. s., 1H), 4.79 (br. s., 1H), 4.64 (br. s., 1H), 4.37- 4.22 (m,2H), 4.28 (d, 2H, J = 5.6 Hz), 4.02 (s, 2H), 3.62 (s, 3H), 3.57 (t, 2H,J = 6.0 Hz), 3.32 (s, 3H), 2.45 (s, 2H), 2.26 (s, 3H) 236 2 ¹H NMR (400MHz, DMSO-d6) δ 8.39 (d, J = 7.9 Hz, 491 1H), 7.87-7.72 (m, 2H),7.40-7.27 (m, 2H), 7.20-7.07 (m, 2H), 6.76 (d, J = 2.8 Hz, 1H), 6.20 (d,J = 4.7 Hz, 1H), 5.02-4.89 (m, 1H), 4.76 (s, 1H), 4.32 (br.s, 2H), 4.14-4.03 (m, 2H), 3.95 (br.s, 1H), 3.70-3.54 (m, 2H), 2.43- 2.28 (m, 3H),1.56 (s, 3H), 1.37 (d, J = 7.0 Hz, 3H), 0.99 (q, J = 7.2 Hz, 3H). 237 2¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.64-8.62 (m, 1H), 492 8.11 (s, 1H),7.80 (s, 1H), 7.67 (d, 2H, J = 8.4 Hz), 7.40- 7.38 (m, 1H), 7.23-7.18(m, 1H), 7.08-7.03 (m, 2H), 6.95 (d, 2H, J = 8.4 Hz), 4.73-4.63 (m, 2H),4.32 (d, 2H, J = 5.2 Hz), 4.29-4.19 (m, 2H), 3.64-3.59 (m, 1H), 1.29 (s,9H) 238 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.60 (d, 1H, J = 492 8.0 Hz),8.04 (s, 1H), 7.93 (d, 1H, J = 1.6 Hz), 7.77 (s, 1H), 7.16 (s, 1H),7.37-7.33 (m, 2H), 7.16-7.12 (m, 2H), 6.89 (s, 1H), 5.00-4.93 (m, 1H),4.68-4.53 (m, 3H), 4.33 (br. s., 1H), 4.20-4.15 (m, 2H), 3.63-3.59 (m,1H), 1.44 (d, 3H, J = 7.2 Hz), 1.35 (d, 3H, J = 7.2 Hz), 1.04 (s, 3H),0.99 (s, 3H) 239 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.60 (d, 1H, J = 4928.0 Hz), 8.04 (s, 1H), 7.93 (d, 1H, J = 1.6 Hz), 7.78 (s, 1H), 7.77 (s,1H), 7.37-7.34 (m, 2H), 7.17-7.12 (m, 2H), 6.90 (s, 1H), 5.00-4.93 (m,1H), 4.67-4.53 (m, 3H), 4.33 (br. s., 1H), 4.20-4.15 (m, 2H), 3.66-3.56(m, 1H), 1.44 (d, 3H, J = 7.2 Hz), 1.35 (d, 3H, J = 7.2 Hz), 1.04 (s,3H), 0.99 (s, 3H) 240 2 ¹H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 8.1 Hz,492 1H), 7.79 (m, 3H), 7.43-7.34 (m, 2H), 7.34-7.27 (m, 2H), 6.74 (s,1H), 4.95 (m, 1H), 4.54 (m, 5H), 4.05 (t, J = 7.3 Hz, 2H), 3.60 (ddd, J= 14.4, 8.8, 5.7 Hz, 1H), 3.41 (dt, J = 11.3, 5.9 Hz, 1H), 3.01 (t, J =7.3 Hz, 2H), 2.58 (m, 2H), 1.93-1.70 (m, 2H). 241 2 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.58 (d, 1H, J = 492 8.0 Hz), 8.29 (s, 1H), 7.96 (s, 1H),7.95 (s, 1H), 7.80 (s, 1H), 7.39 (d, 2H, J = 8.8 Hz), 7.33 (d, 2H, J =8.8 Hz), 6.94 (s, 1H), 5.57-5.54 (m, 1H), 4.96-4.87 (m, 4H), 4.75- 4.00(m, 5H), 3.68-3.64 (m, 1H), 1.71-1.66 (m, 2H), 0.85(t, 3H, J = 7.2 Hz)242 2 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.92 (s, 1H), 7.75 (s, 492 1H), 7.68(s, 1H), 7.60 (s, 1H), 7.31-7.29 (m, 2H), 7.24- 7.22 (m, 2H), 6.83 (s,1H), 4.81 (q, 1H, J = 8.0 Hz), 4.56- 4.50 (m, 1H), 4.42 (br.s, 2H),1.86-1.78 (m, 2H), 1.71 (br.s, 3H), 1.55 (d, 6H, J = 6.4 Hz), 0.90 (t,3H, J = 7.2 Hz) 243 1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (d, J = 8.0 Hz,1H), 493 7.99 (s, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.77 (d, J = 5.4 Hz,2H), 7.41-7.27 (m, 4H), 6.84 (d, J = 1.8 Hz, 1H), 4.72 (dq, J = 19.4,10.5, 8.9 Hz, 2H), 4.45 (d, J = 9.0 Hz, 1H), 4.11 (s, 1H), 3.83 (s, 3H),3.00 (s, 2H), 2.32 (s, 3H), 1.70 (p, J = 7.3 Hz, 2H), 0.85 (t, J = 7.3Hz, 3H) 244 3 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.71-7.67 (m, 4H), 4947.11-7.09 (m, 2H), 6.96-6.85 (m, 3H), 4.97 (br.s, 2H), 4.79-4.47 (m,4H), 4.29-4.14 (m, 3H), 3.65 (s, 1H), 3.55 (s, 1H), 3.33 (s, 3H), 1.40(d, 3H, J = 6.8 Hz) 245 1 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.58 (d, 1H, J= 494 8.0 Hz), 8.36 (s, 1H), 8.05 (d, 2H, J = 8.0 Hz), 7.89-7.84 (m,3H), 7.34-7.33 (m, 2H), 7.25 (s, 1H), 7.14 (t, 2H, J = 8.8 Hz),5.00-4.96 (m, 1H), 4.76-4.72 (m, 2H), 4.36-4.31 (m, 2H), 3.65-3.60 (m,1H), 3.21 (s, 3H), 1.35 (d, 3H, J = 7.2 Hz) 246 2 ¹H-NMR (400 MHz,CDCl₃) δ ppm 7.98 (s, 1H), 7.90 (s, 494 1H), 7.59-7.53 (m, 3H),7.33-7.29 (m, 1H), 7.14-7.09 (m, 3H) 6.96 (br.s, 1H), 5.19 (br.s, 1H),5.04 (br.s, 1H), 4.85 (br.s, 1H), 4.70 (br.s, 1H), 4.51 (br.s, 2H),3.74-3.71 (m, 1H), 1.63 (s, 6H) 247 2 ¹H NMR (400 MHz, DMSO-d6) δ 8.52(d, J = 8.1 Hz, 494 1H), 7.99 (s, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.78(s, 1H), 7.77 (d, J = 0.8 Hz, 1H), 7.43-7.34 (m, 2H), 7.34-7.26 (m, 2H),6.85 (d, J = 1.7 Hz, 1H), 5.07-5.02 (m, 1H), 4.74- 4.47 (m, 2H), 4.41(s, 1H), 4.19 (s, 2H), 3.83 (s, 3H), 3.58 (ddd, J = 14.4, 8.7, 5.6 Hz,1H), 1.89 (dd, J = 14.3, 9.1 Hz, 1H), 1.70 (dd, J = 14.3, 3.5 Hz, 1H),1.09 (2 very closely spaced singlets, 6H). 248 3 ¹H-NMR (400 MHz, CD₃OD)δ ppm 8.71 (d, 1H, J = 8.0 494 Hz), 8.07 (s, 1H), 7.99 (br.s, 1H), 7.88(s, 1H), 7.85 (s, 1H), 7.35-7.25 (m, 5H), 5.00-4.98 (m, 1H), 4.82-4.60(m, 4H), 4.16-4.07 (m, 3H), 3.84-3.79 (m, 1H), 1.87-1.78 (m, 2H), 1.18(d, 3H, J = 5.6 Hz), 0.93 (t, 3H, J = 7.2 Hz) 249 2 ¹H-NMR (400 MHz,CD₃OD) δ ppm 8.69 (d, 1H, J = 8.0 494 Hz), 8.10 (s, 1H), 8.00 (s, 1H),7.90 (s, 1H), 7.84 (s, 1H), 7.35-7.30 (m, 5H), 4.96-4.90 (m, 3H),4.67-4.48 (m, 2H), 4.35-4.30 (m, 2H), 3.85-3.80 (m, 1H), 3.76-3.74 (m,2H), 3.32 (s, 3H), 1.85-1.80 (m, 2H), 0.93 (t, 3H, J = 7.2 Hz) 250 2¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.62 (d, 1H, J = 494 7.6 Hz), 8.00 (s,1H), 7.94 (d, 1H, J = 1.2 Hz), 7.80 (s, 1H), 7.79 (s, 1H), 7.39 (d, 2H,J = 8.8 Hz), 7.34 (d, 2H, J = 8.4 Hz), 6.90 (s, 1H), 4.98-4.94 (m, 1H),4.74 (s, 1H), 4.73-3.99 (m, 4H), 4.00 (s, 2H), 3.64-3.58 (m, 1H), 1.36(d, 3H, J = 7.2 Hz), 1.08 (s, 6H) 251 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm8.57 (d, 1H, J = 494 8.4 Hz), 8.01 (s, 1H), 7.93 (d, 1H, J = 1.6 Hz),7.80 (s, 1H), 7.79 (s, 1H), 7.39 (d, 2H, J = 8.4 Hz), 7.32 (d, 2H, J =8.8 Hz), 6.89 (s, 1H), 4.95 (d, 1H, J = 4.4 Hz), 4.79-4.08 (m, 5H), 3.97(s, 3H), 3.69-3.59 (m, 1H), 1.77-1.62 (m, 2H), 1.04 (d, 3H, J = 5.6 Hz),0.85 (t, 3H, J = 7.2 Hz) 252 2 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.79 (s,1H), 7.75 (s, 495 1H), 7.54-7.48 (m, 4H), 7.14-7.08 (m, 4H), 6.67 (s,1H), 5.96 (br.s, 1H), 4.39 (d, 2H, J = 5.6 Hz), 3.60-3.56 (m, 2H),3.44-3.42 (m, 3H), 2.28 (s, 3H), 1.92-1.81 (m, 4H) 253 2 ¹H-NMR (400MHz, CDCl₃) δ ppm 7.92 (s, 1H), 7.88 (s, 495 1H), 7.62 (d, 2H, J = 8.0Hz), 7.53 (d, 2H, J = 8.0 Hz), 7.11-7.05 (m, 5H), 6.96 (br.s, 1H),4.44-4.149 (m, 10H), 2.35-2.28 (m, 2H), 2.25 (s, 3H), 1.67 (s, 3H) 254 3¹H-NMR (400 MHz, CDCl₃) δ ppm 7.78 (s, 1H), 7.75 (d, 495 1H, J = 1.2Hz), 7.59 (d, 2H, J = 8.8 Hz), 7.50 (d, 2H, J = 8.8 Hz), 7.13-7.08 (m,4H), 6.71 (s, 1H), 5.95 (br.s, 1H), 4.40 (d, 2H, J = 5.6 Hz), 4.19(br.s, 1H), 3.83 (t, 2H, J = 7.2 Hz), 2.56 (t, 2H, J = 8.4 Hz), 2.27 (s,3H), 2.20-2.05 (m, 2H), 1.64 (br.s, 3H) 255 2 ¹H-NMR (400 MHz, CDCl₃) δppm 7.85 (s, 1H), 7.60 (s, 495 1H), 7.36-7.27 (m, 2H), 7.25-7.16 (m,2H), 6.66 (s, 1H), 6.53 (br.s, 1H), 6.05 (br.s, 1H), 4.45 (d, 2H, J =5.2 Hz), 4.29 (d, 2H, J = 9.2 Hz), 4.12 (br.s, 2H), 3.74 (s, 3H), 3.69(br.s, 2H), 2.47 (br.s, 2H), 1.71 (s, 3H) 256 2 496 257 1 ¹H-NMR (400MHz, DMSO-d₆) δ ppm 8.90 (t, 1H, J = 6.0 497 Hz), 8.00 (s, 1H), 7.95 (d,1H, J = 1.6 Hz), 7.82 (s, 1H), 7.78 (d, 1H, J = 1.2 Hz), 7.53-7.50 (m,2H), 7.25-7.23 (m, 2H), 6.95 (d, 1H, J = 1.6 Hz), 4.80, 4.65 (br. s.,2H), 4.36, 4.22 (br. s., 2H), 4.30 (d, 2H, J = 6.4 Hz), 3.84 (s, 3H),3.31 (s, 3H) 258 2 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.85 (s, 1H), 7.61 (s,497 1H), 7.31-7.21 (m, 1H), 6.85 (br.s, 1H), 6.82-6.66 (m, 3H), 6.02(br.s, 1H), 4.41 (d, 2H, J = 4.0 Hz), 4.36 (br.s, 2H), 4.06 (br.s, 2H),3.68 (s, 3H), 3.63 (br.s, 2H), 2.40 (br.s, 2H), 1.65 (s, 3H) 259 2¹H-NMR (400 MHz, CD₃OD) δ ppm 7.92 (s, 1H), 7.78 (s, 498 2H), 7.72 (s,1H), 7.38 (t, 1H, J = 8.0 Hz), 7.21-7.19 (m, 2H), 6.87 (s, 1H), 4.45 (s,2H), 4.10 (s, 2H), 3.73-3.64 (m, 1H), 1.19 (s, 6H) 260 3 ¹H-NMR (400MHz, CDCl₃) δ ppm 7.83 (s, 1H), 7.75 (s, 499 1H), 7.59-7.57 (m, 2H),7.51-7.49 (m, 2H), 7.27-7.25 (m, 2H), 6.99-6.95 (m, 2H), 6.74 (s, 1H),6.18 (d, 1H, J = 6.8 Hz), 5.09-5.06 (m, 1H), 4.54 (br.s, 2H), 3.85-3.82(m, 3H), 2.56 (t, 2H, J = 8.0 Hz), 2.15-2.13 (m, 2H), 1.45 (d, 3H, J =6.4 Hz) 261 2 ¹H-NMR (400 MHz, CD₃OD) δ 8.27 (s, 1H), 7.89 (s, 1H), 4997.82 (d, 2H, J = 7.6 Hz), 7.68 (d, 2H, J = 8.0 Hz), 7.42 (s, 1H),7.38-7.35 (m, 2H), 7.08-7.03 (m, 2H), 5.07-5.03 (m, 3H), 4.64 (br.s,2H), 4.42-4.40 (m, 2H), 4.23-4.19 (m, 2H), 3.79-3.78 (m, 1H), 2.42-2.36(m, 2H), 1.47 (d, 3H, J = 7.2 Hz) 262 2 ¹H-NMR (400 MHz, CD₃OD) δ ppm8.69 (d, 1H, J = 6.8 499 Hz), 7.88 (s, 2H), 7.38-7.34 (m, 2H), 7.08-7.03(m, 2H), 5.06 (br.s, 1H), 4.90 (br.s, 2H), 3.93 (s, 1H), 3.78 (br.s, 2H), 3.49 (s, 1H), 3.34 (s, 1H), 2.92 (s, 3H), 2.62 (br.s, 1H), 1.47 (d,3H, J = 7.2 Hz) 263 2 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.79 (s, 1H), 7.51(s, 499 1H), 7.25 (t, 1H, J = 8.0 Hz), 7.05 (t, 2H, J = 7.2 Hz), 6.50(s, 1H), 5.99 (br.s, 2H), 4.55 (br.s, 4H), 4.44 (d, 2H, J = 6.0 Hz),4.05 (br.s, 2H), 3.67 (s, 3H), 3.62 (br.s, 2H), 3.46- 3.43 (m, 1H), 2.41(br.s, 2H) 264 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.80 (t, 1H, J = 6.0500 Hz), 8.16 (s, 1H), 7.84 (s, 1H), 7.70 (d, 2H, J = 8.4 Hz), 7.17-7.11(m, 5H), 6.98 (d, 2H, J = 8.4 Hz), 4.85 (br. s., 1H), 4.70 (br. s., 1H),4.29-4.23 (m, 4H), 3.33 (s, 3H), 2.26 (s, 3H), 1.30 (s, 9H) 265 2 ¹H NMR(400 MHz, DMSO-d6) δ 8.58 (t, J = 5.9 Hz, 1H), 500 7.86-7.70 (m, 2H),7.19-7.07 (m, 4H), 6.79 (d, J = 1.7 Hz, 1H), 6.22-6.15 (m, 1H),4.74-4.52 (m, 2H), 4.23 (m, 4H), 3.83 (dt, J = 5.3, 2.6 Hz, 2H),3.65-3.54 (m, 1H), 3.36 (t, J = 5.6 Hz, 2H), 2.26 (s, 3H), 1.74 (m,4H)-one peak partially hidden by water signal. 266 2 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.56 (d, 1H, J = 502 8.0 Hz), 7.81 (s, 1H), 7.79 (d, 1H,J = 8.0 Hz), 7.38 (d, 2H, J = 8.0 Hz), 7.31 (d, 2H, J = 8.0 Hz), 6.79(s, 1H), 6.09 (s, 1H), 4.94 (q, 1H, J = 8.0 Hz), 4.80-4.43 (m, 2H), 4.53(t, 1H, J = 4.0 Hz), 4.42-4.02 (br m, 2H), 3.63-3.55 (m, 1H), 3.43-3.29(m, 2H), 2.74-2.57 (m, 4H), 2.20-2.08 (m, 2H), 1.90-1.71 (m, 2H) 267 2¹H NMR (300 MHz, DMSO-d6) δ 8.61 (t, J = 5.9 Hz, 1H), 503 7.80 (d, J =4.8 Hz, 2H), 7.15 (d, J = 2.0 Hz, 4H), 6.81 (d, J = 1.7 Hz, 1H), 6.20(s, 1H), 4.78-4.49 (m, 2H), 4.28 (m, 4H), 3.98 (s, 2H), 3.60 (d, J = 5.6Hz, 1H), 3.58-3.47 (m, 2H), 2.28 (s, 3H), 1.42 (s, 9H). 268 2 ¹H NMR(400 MHz, DMSO-d₆) δ 9.07-8.68 (m, 1H), 503 8.10-7.58 (m, 4H), 7.25-6.96(m, 4H), 6.84 (d, J = 1.7 Hz, 1H), 4.71 (m, 2H), 4.53 (s, 1H), 4.31 (d,J = 5.9 Hz, 3H), 4.17 (s, 1H), 3.99 (s, 2H), 3.19 (s, 2H), 2.41 (s, 3H),2.26 (s, 3H), 1.07 (s, 6H) 269 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.52(d, 1H, J = 504 8.4 Hz), 8.06 (s, 1H), 7.78 (s, 1H), 7.65 (d, 2H, J =8.4 Hz), 7.38-7.30 (m, 4H), 6.98 (s, 1H), 6.89 (d, 2H, J = 8.4 Hz),4.75-4.71 (m, 1H), 4.64-4.58 (m, 1H), 4.50-4.05 (m, 4H), 3.65-3.55 (m,1H), 1.67 (q, 2H, J = 7.2 Hz), 1.25 (d, 6H, J = 6.0 Hz), 0.83 (t, 3H, J= 7.2 Hz) 270 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.56 (d, 1H, J = 504 8.4Hz), 8.19 (s, 1H), 7.85 (s, 1H), 7.69 (d, 2H, J = 7.6 Hz), 7.45 (d, 1H,J = 8.4 Hz), 7.39-7.31 (m, 4H), 7.13 (s, 1H), 4.76-4.70 (m, 1H),4.37-4.14 (m, 4H), 3.65-3.60 (m, 1H), 1.70-1.64 (m, 2H), 1.42 (s, 6H),0.84 (t, 3H, J = 7.2 Hz) 271 2 ¹H-NMR (400 MHz, CD₃OD) δ ppm 7.87 (s,1H), 7.72 (s, 504 1H), 7.58 (d, 2H, J = 8.0 Hz), 7.32 (s, 4H), 7.01 (d,2H, J = 8.4 Hz), 6.94 (s, 1H), 5.06-5.01 (m, 1H), 3.71-3.64 (m, 1H),1.46 (d, 3H, J = 6.8 Hz), 1.35 (s, 9H) 272 2 ¹H NMR (300 MHz, DMSO-d6) δ8.63 (t, J = 5.8 Hz, 1H), 506 8.23 (d, J = 1.6 Hz, 1H), 7.89-7.76 (m,2H), 7.46 (d, J = 8.0 Hz, 2H), 7.24-7.09 (m, 4H), 4.72 (d, J = 26.2 Hz,2H), 4.50-4.13 (m, 4H), 3.64 (dd, J = 10.1, 5.3 Hz, 1H), 2.28 (s, 2H),1.39-1.29 (m, 2H), 1.15 (d, J = 5.2 Hz, 2H). 273 3 ¹H-NMR (400 MHz,CD₃OD) δ ppm 7.90 (s, 1H), 7.72 (s, 506 1H), 7.47-7.40 (m, 1H),7.37-7.34 (m, 3H), 7.10-7.03 (3H, m), 6.96 (s, 1H), 5.08-5.03 (m, 1H),4.90 (br.s, 2H), 4.58 (br.s, 2H), 3.69-3.66 (m, 1H), 1.47 (d, J = 6.8Hz), 1.36 (s, 9H) 274 1 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.81 (t, 1H, J =5.6 506 Hz), 8.42 (d, 1H, J = 1.6 Hz), 8.08 (d, 2H, J = 8.4 Hz), 7.90(d, 2H, J = 8.4 Hz), 7.89 (s, 1H), 7.34 (d, 1H, J = 1.6 Hz), 7.16 (d,2H, J = 8.0 Hz), 7.11 (d, 2H, J = 8.0 Hz), 4.91-4.88 (m, 1H), 4.74-4.71(m, 1H), 4.42-4.26 (m, 4H), 3.34 (s, 3H), 3.23 (s, 3H), 2.26 (s, 3H) 2753 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.59 (d, 1H, J = 506 8.4 Hz), 8.17 (s,1H), 7.82 (s, 1H), 7.72 (d, 2H, J = 7.6 Hz), 7.39 (d, 2H, J = 8.0 Hz),7.34-7.32 (m, 4H), 7.09 (s, 1H), 5.23 (d, 1H, J = 4.4 Hz), 4.76-4.71 (m,3H), 4.55- 4.52 (m, 1H), 4.32-4.10 (br, 2H), 3.68-3.64 (m, 1H), 3.44-3.41 (m, 2H), 3.34-3.33 (m, 1H), 1.71-1.65 (m, 2H), 0.85 (t, 3H, J = 7.2Hz) 276 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.58 (d, 1H, J = 506 8.0 Hz),8.18 (s, 1H), 7.82 (s, 1H), 7.73 (d, 2H, J = 6.4 Hz), 7.41-7.33 (m, 6H),7.09 (s, 1H), 5.23 (s, 1H), 4.75- 4.72 (m, 3H), 4.56-4.52 (m, 2H),4.40-4.00 (br, 2H), 3.65 (br. s, 1H), 3.43 (br. s., 1H), 3.34-3.31 (m,1H), 1.72-1.68 (m, 2H), 0.85 (s, 3H) 277 2 ¹H-NMR (400 MHz, DMSO-d₆) δppm 10.31 (s, 1H), 8.15 507 (s, 1H), 7.83 (s, 1H), 7.68 (d, 2H, J = 8.4Hz), 7.60 (d, 2H, J = 9.2 Hz), 7.49 (d, 2H, J = 8.8 Hz), 7.44 (d, 2H, J= 8.4 Hz), 7.08 (s, 1H), 4.98 (s, 1H), 4.80-4.70 (m, 2H), 4.41- 4.29 (m,2H), 3.80-3.75 (m, 1H), 1.42 (s, 6H) 278 3 ¹H-NMR (400 MHz, DMSO-d₆) δppm 8.57 (d, 1H, J = 507 8.4 Hz), 8.16 (s, 1H), 7.93 (s, 1H), 7.81 (s,1H), 7.77 (s, 1H), 7.39 (d, 2H, J = 8.4 Hz), 7.32 (d, 2H, J = 8.4 Hz),6.91 (s, 1H), 4.74-4.00 (m, 5H), 3.70-3.56 (m, 1H), 2.83 (s, 2H),1.70-1.62 (m, 2H), 1.47 (s, 6H), 0.83 (t, 3H, J = 7.2 Hz) 279 2 ¹H NMR(300 MHz, DMSO-d6) δ 8.45 (d, J = 7.8 Hz, 508 1H), 8.40 (d, J = 1.6 Hz,1H), 8.08 (d, J = 8.4 Hz, 2H), 7.96-7.84 (m, 3H), 7.42-7.32 (m, 2H),7.30-7.22 (m, 1H), 7.22-7.09 (m, 2H), 4.98 (m, 1H), 4.88 (d, J = 9.1 Hz,1H), 4.49-4.29 (m, 2H), 4.02 (br.s, 1H), 3.23 (s, 3H), 1.60 (s, 3H),1.39 (d, J = 7.0 Hz, 3H). 280 2 ¹H NMR (300 MHz, DMSO-d₆) δ 8.62 (t, J =5.8 Hz, 1H), 508 8.19 (d, J = 1.7 Hz, 1H), 7.86 (s, 1H), 7.75-7.66 (m,2H), 7.52-7.24 (m, 5H), 7.13-7.03 (m, 1H), 4.98-4.76 (m, 2H), 4.49-4.30(m, 4H), 4.07-3.94 (m, 1H), 1.61 (s, 3H), 1.44 (s, 6H) 281 2 ¹H-NMR (400MHz, DMSO-d₆) δ ppm 8.55 (d, 1H, J = 508 7.6 Hz), 8.05 (s, 1H), 8.01 (s,1H), 7.88 (s, 1H), 7.80 (s, 1H), 7.38-7.30 (m, 4H), 7.06 (br.s, 1H),4.75-4.70 (m, 1H), 3.98 (s, 2H), 3.70-3.60 (m, 1H), 1.70-1.64 (m, 2H),1.06 (s, 6H), 0.83 (t, 3H, J = 7.2 Hz) 282 3 ¹H-NMR (400 MHz, DMSO-d₆) δppm 8.58 (d, 1H, J = 508 8.4 Hz), 8.02 (s, 1H), 7.93 (d, 1H, J = 1.6Hz), 7.80 (s, 1H), 7.79 (s, 1H), 7.39 (d, 2H, J = 8.4 Hz), 7.33 (d, 2H,J = 8.4 Hz), 6.89 (s, 1H), 4.92 (d, 1H, J = 5.2 Hz), 4.81-4.45 (m, 3H),4.44-3.92 (m, 4H), 3.79-3.69 (m, 1H), 3.68-3.58 (m, 1H), 1.74-1.60 (m,2H), 1.45-1.21 (m, 2H), 0.89 (t, 3H, J = 7.2 Hz), 0.85 (t, 3H, J = 7.2Hz) 283 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.62 (d, 1H, J = 508 8.4 Hz),8.18 (s, 1H), 8.04 (s, 1H), 7.88 (s, 1H), 7.83 (s, 1H), 7.40 (d, 2H, J =8.4 Hz), 7.33 (d, 2H, J = 8.0 Hz), 7.07 (s, 1H), 4.77-4.71 (m, 1H),4.67-4.10 (m, 5H), 3.70- 3.66 (m, 1H), 3.58 (s, 2H), 1.71-1.67 (m, 2H),1.48 (s, 6H), 0.85 (t, 3H, J = 7.2 Hz) 284 3 ¹H-NMR (400 MHz, DMSO-d₆) δppm 8.58 (d, 1H, J = 508 8.4 Hz), 8.06 (s, 1H), 7.91 (d, 1H, J = 1.6Hz), 7.78 (s, 1H), 7.77 (s, 1H), 7.38 (d, 2H, J = 8.4 Hz), 7.31 (d, 2H,J = 8.4 Hz), 6.88 (s, 1H), 4.97 (d, 1H, J = 5.2 Hz), 4.76-4.54 (m, 3H),4.35-4.30 (br, 1H), 4.18-4.04 (m, 2H), 3.82-3.78 (m, 1H), 3.67-3.60 (m,1H), 1.69-1.66 (m, 2H), 1.44 (d, 3H, J = 7.2 Hz), 0.87 (d, 3H, J = 6.0Hz), 0.83 (t, 3H, J = 7.2 Hz) 285 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.57(d, 1H, J = 508 8.0 Hz), 8.06 (s, 1H), 7.91 (d, 1H, J = 1.6 Hz), 7.78(s, 1H), 7.77 (s, 1H), 7.38 (d, 2H, J = 8.4 Hz), 7.32 (d, 2H, J = 8.8Hz), 6.89 (s, 1H), 4.96 (d, 1H, J = 5.6 Hz), 4.76-4.49 (m, 3H),4.36-4.30 (br, 1H), 4.18-4.03 (m, 2H), 3.82-3.78 (m, 1H), 3.65-3.61 (m,1H), 1.71-1.64 (m, 2H), 1.44 (d, 3H, J = 6.8 Hz), 0.87 (d, 6H, J = 6.8Hz), 0.83 (t, 6H, J = 7.2 Hz) 286 2 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.80(s, 1H), 7.53 (s, 508 1H), 7.31 (d, 2H, J = 8.4 Hz), 7.21 (d, 2H, J =8.0 Hz), 6.49 (s, 1H), 6.00 (br.s, 1H), 5.77 (d, 1H, J = 7.6 Hz),4.91-4.85 (m, 1H), 4.75-4.35 (m, 4H), 4.10 (br.s, 2H), 3.73 (s, 3H),3.67 (br.s, 2H), 3.51-3.43 (m, 1H), 2.47 (br.s, 2H), 1.88-1.79 (m, 2H),0.90 (t, 3H, J = 7.2 Hz) 287 2 ¹H NMR (400 MHz, DMSO-d6) δ 8.60 (t, J =5.9 Hz, 1H), 510 8.21 (d, J = 1.7 Hz, 1H), 7.83 (s, 1H), 7.82-7.75 (m,2H), 7.57 (d, J = 8.1 Hz, 2H), 7.24-7.05 (m, 5H), 6.56 (s, 1H), 4.72 (d,J = 35.9 Hz, 2H), 4.40-4.16 (m, 4H), 3.63 (ddd, J = 14.5, 8.8, 5.8 Hz,1H), 2.27 (s, 3H), 1.70 (s, 3H). 288 2 1H-NMR (400 MHz, CD3OD) δ ppm8.17 (s, 1H), 7.88 (s, 510 1H), 7.68 (d, 2H, J = 8.4 Hz), 7.53 (d, 2H, J= 8.0 Hz), 7.47 (s, 1H), 7.36-7.32 (m, 3H), 4.74 (br.s, 1H), 3.75 (s,2H), 1.54 (s, 6H) 289 2 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.92 (s, 1H), 7.66(s, 513 1H), 7.31 (d, 1H, J = 8.0 Hz), 7.13-7.07 (m, 2H), 6.85 (br.s,1H), 6.77 (s, 1H), 6.08 (br.s, 1H), 4.50 (d, 2H, J = 5.2 Hz), 4.38 (d,2H, J = 9.6 Hz), 4.14 (br.s, 2H), 3.75 (s, 3H), 2.48 (br.s, 2H), 1.72(s, 3H) 290 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.49 (d, 1H, J = 514 8.0Hz), 8.11 (s, 1H), 7.80 (s, 1H), 7.68 (d, 2H, J = 8.0 Hz), 7.18 (d, 2H,J = 8.0 Hz), 7.12 (d, 2H, J = 8.0 Hz), 7.03 (s, 1H), 6.96 (d, 2H, J =8.0 Hz), 4.92 (q, 1H, J = 8.0 Hz), 4.80-4.48 (br m, 2H), 4.48 (t, 1H, J= 4.0 Hz), 4.41- 4.04 (br m, 2H), 3.65-3.57 (m, 1H), 3.42-3.27 (m, 2H),2.26 (s, 3H), 1.93-1.73 (m, 2H), 1.29 (s, 9H) 291 1 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.67 (s, 1H), 8.37 514 (s, 1H), 8.07-8.05 (m, 2H),7.90-7.85 (m, 2H), 7.42-7.37 (m, 2H) 7.28-7.26 (m, 2H) , 4.78-4.68 (m,2H), 4.34-4.33 (m, 2H), 4.20 (br.s, 2H), 3.64 (br.s, 1H), 3.21 (s, 3H)292 2 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.89 (s, 1H), 7.67 (s, 515 1H), 7.43(s, 1H), 7.28 (s, 2H), 6.76 (s, 1H), 6.64 (br.s, 1H), 4.62 (br.s, 1H),4.13 (br.s, 2H), 3.74 (s, 3H), 3.70 (s, 4H), 2.46 (br.s, 2H) 293 3¹H-NMR (400 MHz, CD₃OD) δ ppm 8.62 (d, 1H, J = 7.6 516 Hz), 7.97 (s,1H), 7.75 (s, 1H), 7.67 (d, 2H, J = 8.4 Hz), 7.52 (d, 2H, J = 7.6 Hz),7.34-7.29 (m, 4H), 7.06 (s, 1H), 4.85-4.80 (m, 3H), 4.50-4.40 (m, 2H),3.73-3.70 (m, 1H), 2.54-2.53 (m, 2H), 2.40-2.33 (m, 2H), 2.02-2.00 (m,1H), 1.82-1.72 (m, 3H), 0.93 (t, 3H, J = 7.2 Hz) 294 2 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.54 (d, 1H, J = 518 8.0 Hz), 8.11 (s, 1H), 7.80 (s, 1H),7.67 (d, 2H, J = 8.4 Hz), 7.39-7.31 (m, 4H), 7.03 (s, 1H), 6.96 (d, 2H,J = 8.4 Hz), 4.76-4.70 (m, 1H), 4.30-4.25 (m, 2H), 4.19-4.10 (m, 2H),3.66-3.62 (m, 1H), 1.69-1.66 (m, 2H), 1.29 (s, 9H), 0.83 (t, 3H, J = 7.2Hz) 295 2 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.85 (s, 1H), 7.82 (s, 518 1H),7.57-7.51 (m, 4H), 7.33-7.20 (m, 4H), 6.75 (s, 1H), 5.78 (d, 1H, J = 7.6Hz), 4.88 (q, 1H, J = 7.6 Hz), 4.21 (br.s, 2H), 1.89-1.82 (m, 2H), 1.69(s, 3H), 1.61 (s, 6H), 0.92 (t, 3H, J = 7.6 Hz) 296 2 ¹H-NMR (400 MHz,CDCl₃) δ ppm 7.78 (s, 1H), 7.72 (s, 518 1H), 7.40 (d, 2H, J = 8.4 Hz),7.25 (d, 2H, J = 8.4 Hz), 7.17 (d, 2H, J = 8.4 Hz), 6.95 (d, 2H, J = 8.8Hz), 6.67 (s, 1H), 5.76 (d, 1H, J = 7.2 Hz), 5.10-5.03 (m, 1H), 4.16(br.s, 2H), 1.62 (s, 3H), 1.45 (d, 3H, J = 6.8 Hz), 1.30 (s, 9H) 297 3¹H-NMR (400 MHz, CD₃OD) δ ppm 8.60 (d, 1H, J = 8.0 518 Hz), 7.91 (s,1H), 7.71 (s, 1H), 7.61 (d, 2H, J = 8.4 Hz), 7.43 (d, 2H, J = 8.4 Hz),7.34-7.28 (m, 4H), 6.99 (s, 1H), 480-4.78 (m, 3H), 4.50-4.40 (m, 2H),3.71-3.68 (m, 1H), 1.84-1.77 (m, 4H), 1.51 (s, 3H), 0.92 (t, 3H, J = 7.2Hz), 0.78 (t, 3H, J = 7.2 Hz) 298 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.58(d, 1H, J = 522 8.2 Hz), 8.07 (s, 1H), 7.91 (d, 1H, J = 1.2 Hz), 7.78(s, 2H), 7.40 (d, 2H, J = 8.4 Hz), 7.33 (d, 2H, J = 8.4 Hz), 6.89 (s,1H), 4.81-3.91 (m, 8H), 3.67-3.64 (m, 1H), 1.91 (t, 2H, J = 8.4 Hz),1.71-1.65 (m, 2H), 1.13 (s, 6H), 0.85 (t, 3H, J = 7.2 Hz) 299 3 ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 8.59 (d, 1H, J = 522 8.4 Hz), 8.05 (s, 1H),7.94 (d, 1H, J = 1.6 Hz), 7.79 (s, 1H), 7.78 (s, 1H), 7.39 (d, 2H, J =8.4 Hz), 7.33 (d, 2H, J = 8.4 Hz), 6.91 (s, 1H), 4.77-4.53 (m, 4H),4.38-4.33 (br, 1H), 4.21-4.08 (m, 2H), 3.67-3.62 (m, 1H), 1.72-1.65 (m,2H), 1.45 (d, 3H, J = 6.8 Hz), 1.05 (s, 3H), 1.0 (s, 3H), 0.85 (t, 3H, J= 7.2 Hz) 300 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.59 (d, 1H, J = 522 8.0Hz), 8.05 (s, 1H), 7.94 (d, 1H, J = 1.6 Hz), 7.79 (s, 1H), 7.78 (s, 1H),7.39 (d, 2H, J = 8.8 Hz), 7.33 (d, 2H, J = 8.4 Hz), 6.91 (s, 1H),4.77-4.51 (m, 4 H), 4.38-4.33 (br, 1H), 4.21-4.07 (m, 2H), 3.66-3.63 (m,1 H), 1.70-1.65 (m, 2H), 1.45 (d, 3H, J = 6.8 Hz), 1.05 (s, 3H), 1.0 (s,3H), 0.85 (t, 3H, J = 7.2 Hz) 301 3 ¹H NMR (400 MHz, DMSO-d6) δ 8.56 (d,J = 8.1 Hz, 523 1H), 7.83-7.73 (m, 2H), 7.41-7.35 (m, 2H), 7.34-7.27 (m,2H), 6.79 (s, 1H), 6.20 (s, 1H), 4.94 (m, 1H), 4.78- 4.13 (m, 6H), 4.08(d, J = 12.7 Hz, 2H), 3.68-3.55 (m, 3H), 2.43-2.28 (m, 3H), 1.92-1.69(m, 2H), 1.00 (m, 3H) - one signal is partially buried under watersignal. 302 2 ¹H-NMR (400 MHz, CD₃OD) δ ppm 7.69 (s, 1H), 7.63 (s, 5231H), 7.34-7.28 (m, 4H), 6.16 (s, 1H), 6.13 (br.s, 1H), 4.88- 4.76 (m,4H), 4.55-4.50 (m, 1H), 4.15 (q, 2H, J = 7.2 Hz), 4.08 (br.s, 2H), 3.67(br.s, 3H), 2.49 (br.s, 2H), 1.82-1.78 (m, 2H), 1.27 (t, 3H, J = 7.2Hz), 0.92 (t, 3H, J = 7.2 Hz) 303 2 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.74(s, 1H), 7.47 (s, 523 1H), 7.25-7.13 (m, 4H), 6.43 (s, 1H), 5.94 (br.s,1H), 5.82 (d, 1H, J = 8.0 Hz), 4.83-4.78 (m, 1H), 4.63-4.62 (m, 2H),4.09 (br.s, 2H), 4.04 (br.s, 2H), 3.67 (s, 3H), 3.61 (br.s, 2H), 2.40(br.s, 2H), 1.82-1.75 (m, 2H), 1.60 (s, 3H), 0.84 (t, 3H, J = 7.6 Hz)304 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.44 (d, 1H, J = 524 8.4 Hz), 8.10(s, 1H), 7.79 (s, 1H), 7.66 (d, 2H, J = 8.4 Hz), 7.15 (d, 2H, J = 8.0Hz), 7.01-6.99 (m, 3H), 6.95 (d, 2H, J = 8.4 Hz), 4.70-4.64 (m, 2H),4.33-4.07 (m, 3H), 3.65-3.55 (m, 1H), 1.87-1.84 (m, 1H), 1.67-1.64 (m,2H), 1.29 (s, 9H), 0.89 (d, 2H, J = 6.8 Hz), 0.81 (t, 3H, J = 6.8 Hz),0.63-0.59 (m, 2H) 305 1 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.55 (d, 1H, J =524 8.4 Hz), 8.34 (s, 1H), 8.04 (d, 2H, J = 7.6 Hz), 7.87 (d, 2H, J =8.0 Hz), 7.82 (s, 1H), 7.37-8.29 (m, 4H), 7.28 (br.s, 1H), 4.73-4.71 (m,1H), 4.35-4.09 (m, 4H), 3.70-3.60 (m, 1H), 3.19 (s, 3H), 1.68-1.65 (m,2H), 0.82 (t, 3H, J = 7.2 Hz) 306 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.56(d, 1H, J = 524 8.4 Hz), 8.06 (s, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.77(s, 1H), 7.38 (d, 2H, J = 8.8 Hz), 7.32 (d, 2H, J = 8.4 Hz), 6.88 (s,1H), 4.95 (d, 1H, J = 5.6 Hz), 4.76-4.51(m, 3H), 4.36-4.33 (br, 1H),4.09-4.03 (m, 2H), 3.82-3.78 (m, 1H), 3.66-3.61(m, 1H), 1.71-1.64 (m,2H), 1.44 (d, 3H, J = 6.8 Hz), 0.88-0.82 (m, 6H) 307 2 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.85 (d, 1H, J = 524 6.8 Hz), 8.11 (s, 1H), 7.81 (s, 1H),7.68 (d, 2H, J = 8.8 Hz), 7.56 (s, 1H), 7.38 (d, 2H, J = 2.4 Hz), 7.04(s, 1H), 6.95 (d, 2H, J = 8.4 Hz), 4.70 (d, 1H, J = 6.0 Hz), 3.62 (s,2H), 1.28 (s, 9H) 308 2 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.96 (d, 2H, J =8.4 528 Hz), 7.91 (d, 1H, J = 1.2 Hz), 7.88 (s, 1H), 7.75 (d, 2H, J =8.4 Hz), 7.33-7.29 (m, 1H), 7.14-7.10 (m, 2H), 6.84 (s, 1H), 6.14 (br.s., 1H), 5.00-4.80 (br., 2H), 4.52 (d, 2H, J = 5.2 Hz), 4.25 (br. s.,2H), 3.09 (s, 3H), 1.72 (s, 3H) 309 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm8.55 (d, 1H, J = 529 8.4 Hz), 7.90 (s, 1H), 7.86 (s, 1H), 7.36 (d, 2H, J= 1.1 Hz), 7.31 (d, 2H, J = 7.6 Hz), 6.95 (br.s, 1H), 6.26 (br.s, 1H),4.74-4.70 (m, 1H), 4.40-4.30 (m, 2H), 4.23-4.14 (m, 2H), 3.81 (br.s,2H), 3.65-3.60 (m, 1H), 3.35-3.34 (m, 2H), 2.90 (s, 3H), 2.55 (br.s,2H), 1.68-1.65 (m, 2H), 0.82 (t, 3H, J = 7.2 Hz) 310 2 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.57 (d, 1H, J = 534 8.0 Hz), 8.12 (s, 1H), 7.80 (s, 1H),7.68 (d, 2H, J = 8.0 Hz), 7.38 (d, 2H, J = 8.0 Hz), 7.31 (d, 2H, J = 8.0Hz), 7.03 (br s, 1H), 6.96 (d, 2H, J = 8.0 Hz), 4.99-4.92 (m, 1H),4.81-4.53 (br m, 2H), 4.53 (t, 1H, J = 4.0 Hz), 4.41- 4.04 (br m, 2H),3.66-3.57 (m, 1H), 3.45-3.29 (m, 2H), 1.91-1.72 (m, 2H), 1.30 (s, 9H)311 2 ¹H NMR (400 MHz, DMSO-d6) δ 8.46-8.32 (m, 1H), 537 7.86-7.74 (m,2H), 7.42-7.35 (m, 2H), 7.35-7.27 (m, 2H), 6.76 (s, 1H), 6.20 (d, J =4.6 Hz, 1H), 4.99-4.88 (m, 2H), 4.74 (br.s, 1H), 4.56 (t, J = 4.9 Hz,1H), 4.33 (m, 2H), 4.08 (d, J = 12.2 Hz, 2H), 3.96 (br.s, 1H), 3.69-3.56(m, 2H), 2.36 (m, 3H), 1.89 (m, 1H), 1.78 (m, 1H), 1.00 (m, 3H) - onesignal partially buried under water peak. 312 2 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.72 (d, 1H, J = 538 7.6 Hz), 8.00-7.97 (m, 2H), 7.81 (s,1H), 7.79 (br. s., 1H), 7.38 (s, 4H), 6.95 (s, 1H), 4.82-4.21 (m, 6H),3.99 (s, 2H), 3.28 (s, 3H), 1.83-1.67 (m, 2H), 1.07 (s, 6H), 0.85 (t,3H, J = 6.8 Hz) 313 2 ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.97 (d, 2H, J = 8.4538 Hz), 7.94-7.86 (m, 2H), 7.77 (d, 2H, J = 8.4 Hz), 7.34 (d, 2H, J =8.4 Hz), 7.24 (d, 2H, J = 8.4 Hz), 6.82 (d, 1H, J = 1.2 Hz), 5.79 (d,1H, J = 8.4 Hz), 4.93-4.87 (m, 1H), 3.10 (s, 3H), 1.91-1.83 (m, 2H),1.73 (s, 3H), 0.94 (t, 3H, J = 7.2 Hz) 314 2 ¹H-NMR (400 MHz, DMSO-d₆) δppm 8.57 (d, 1H, J = 548 7.6 Hz), 8.11 (s, 1H), 7.94 (s, 1H), 7.87 (s,1H), 7.78 (s, 1H), 7.40 (d, 2H, J = 8.8 Hz), 7.33 (d, 2H, J = 8.4 Hz),6.91 (s, 1H), 6.74 (d, 1H, J = 6.0 Hz), 4.75-4.68 (m, 3H), 4.40-4.36 (m,3H), 4.23-4.18 (m, 2H), 3.66-3.63 (m, 1H), 1.69-1.65 (m, 2H), 0.85 (t,3H, J = 7.6 Hz) 315 2 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.58 (d, 1H, J =548 8.4 Hz), 8.11 (s, 1H), 7.94 (s, 1H), 7.88 (s, 1H), 7.78 (s, 1H),7.39 (d, 2H, J = 8.8 Hz), 7.33 (d, 2H, J = 8.8 Hz), 6.91 (s, 1H), 6.75(s, 1H), 4.74-4.52 (m, 3H), 4.39-4.36 (m, 3H), 4.22-4.16 (m, 1H), 4.06(br. s., 1H), 3.65-3.62 (m, 1H), 1.69-1.65 (m, 2H), 0.83 (t, 3H, J = 7.6Hz) 316 2 ¹H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J = 8.1 Hz, 567 1H),7.83-7.73 (m, 2H), 7.41-7.34 (m, 2H), 7.34-7.27 (m, 2H), 6.78 (s, 1H),6.18 (s, 1H), 4.94 (q, J = 7.8 Hz, 1H), 4.75-4.03 (m, 6H), 3.96 (br.s,2H), 3.60 (td, J = 8.7, 4.4 Hz, 1H), 3.51 (t, J = 5.8 Hz, 2H), 2.41(br.s, 2H), 1.92- 1.69 (m, 2H) - one peak partially obscured by watersignal. 317 2 ¹H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 8.0 Hz, 581 1H),7.83-7.76 (m, 2H), 7.41-7.35 (m, 2H), 7.35-7.29 (m, 2H), 6.76 (s, 1H),6.17 (s, 1H), 4.98-4.90 (m, 1H), 4.74 (br.s, 1H), 4.56 (t, J = 4.9 Hz,1H), 4.30 (br.s, 2H), 3.96 (br.s, 3H), 3.51 (t, J = 5.7 Hz, 2H), 2.42(br.s, 2H), 1.90 (dt, J = 14.2, 7.1 Hz, 1H), 1.79 (dt, J = 13.5, 6.5 Hz,1H), 1.56 (s, 3H), 1.41 (s, 9H).

Biochemical Activity of Compounds

In order to assess the activity of chemical compounds against therelevant kinase of interest, the Caliper LifeSciences electrophoreticmobility shift technology platform is used. Fluorescently labeledsubstrate peptide is incubated in the presence of kinase and ATP so thata reflective proportion of the peptide is phosphorylated. At the end ofthe reaction, the mix of phosphorylated (product) and non-phosphorylated(substrate) peptides are passed through the microfluidic system of theCaliper EZ Reader 2, under an applied potential difference. The presenceof the phosphate group on the product peptide provides a difference inmass and charge between those of the substrate peptide, resulting in aseparation of the substrate and product pools in the sample. As thepools pass a LEDS within the instrument, these pools are detected andresolved as separate peaks. The ratio between these peaks thereforereflects the activity of the chemical matter at that concentration inthat well, under those conditions.

Kit wild type assay at Km: In each well of a 384-well plate, 0.2 ng/ulfinal (2 nM) of wild type Kit (Carna Bioscience 08-156) was incubated ina total of 12.5 ul of buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 10 mMMgCl2, 1 mM DTT) with 1 uM Srctide (5-FAM-GEEPLYWSFPAKKK-NH2) and 400 uMATP at 25 C for 90 minutes in the presence or absence of a dosedconcentration series of compound (1% DMSO final concentration). Thereaction was stopped by the addition of 70 ul of Stop buffer (100 mMHEPES pH 7.5, 0.015% Brij 35, 35 mM EDTA and 0.2% of Coating Reagent 3(Caliper Lifesciences)). The plate was then read on a Caliper EZReader 2(protocol settings: −1.9 psi, upstream voltage −700, downstream voltage−3000, post sample sip 35s). Data was normalized to 0% and 100%inhibition controls and the IC50 or EC50 calculated using a 4-parameterfit using GraphPad Prism.

Kit D816V assay at Km: In each well of a 384-well plate, 0.04 ng/ul (0.5nM) of D816V Kit (Carna Bioscience 08-156) was incubated in a total of12.5 ul of buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 10 mM MgCl2, 1mM DTT) with 1 uM Srctide (5-FAM-GEEPLYWSFPAKKK-NH2) and 15 uM ATP at 25C for 90 minutes in the presence or absence of a dosed concentrationseries of compound (1% DMSO final concentration). The reaction wasstopped by the addition of 70 ul of Stop buffer (100 mM HEPES pH 7.5,0.015% Brij 35, 35 mM EDTA and 0.2% of Coating Reagent 3 (CaliperLifesciences)). The plate was then read on a Caliper EZReader 2(protocol settings: −1.9 psi, upstream voltage −700, downstream voltage−3000, post sample sip 35s). Data was normalized to 0% and 100%inhibition controls and the IC50 or EC50 calculated using a 4-parameterfit using GraphPad Prism.

The Table below shows the activity of compounds described herein,against wild-type Kit and mutant Kit (the D816V mutant). In the Tablebelow, for D816V activity, the following designations are used: <1.00nM=A; 1.01-10.0 nM=B; 10.01-100.0 nM=C; >100 nM=D; and ND=notdetermined. For wild-type Kit activity, the following designations areused: <10 nM=A; 11-100 nM=B; 100-1000 nM=C; >1000 nM=D; and ND=notdetermined.

D816V WT Compound IC₅₀ IC₅₀ Number Structure (nM) (nM)  1

B C  2

A C  3

B C  4

B C  5

A B  6

A B  7

B C  8

B B  9

B C  10

B C  11

B C  12

A C  13

B C  14

A C  15

A C  16

B B  17

A B  18

B B  19

B C  20

B C  21

A C  22

A C  23

A C  24

A C  25

A C  26

B C  27

B C  28

A B  29

A C  30

B C  31

B C  32

B C  33

A C  34

B C  35

B C  36

A B  37

B C  38

A C  39

B C  40

B C  41

B C  42

B C  43

A B  44

B C  45

A C  46

B C  47

A C  48

A B  49

A B  50

B C  51

B C  52

A C  53

B C  54

A C  55

B C  56

A C  57

B C  58

B C  59

B C  60

B C  61

A C  62

B C  63

B C  64

B C  65

B C  66

B C  67

B C  68

B C  69

B C  70

B C  71

B C  72

A C  73

B C  74

A C  75

B C  76

A B  77

A C  78

B C  79

A B  80

A C  81

B C  82

B C  83

B D  84

C B  85

A C  86

B C  87

B C  88

B C  89

A C  90

A C  91

B C  92

A C  93

A C  94

A C  95

B C  96

B C  97

B C  98

B C  99

B C 100

B C 101

B C 102

B C 103

A C 104

B B 105

A C 106

B C 107

A B 108

A C 109

A C 110

B C 111

A B 112

B C 113

B C 114

C C 115

B D 116

A C 117

A C 118

B C 119

A C 120

A B 121

A D 122

A C 123

B B 124

A B 125

A C 126

A C 127

A C 128

B C 129

B C 130

A C 131

B C 132

A C 133

A C 134

A C 135

B C 136

B C 137

B C 138

A C 139

B C 140

B C 141

B C 142

B C 143

A B 144

B C 145

B C 146

A C 147

A C 148

B C 149

B C 150

B C 151

A C 152

B C 153

A B 154

A C 155

A C 156

B C 157

A C 158

A C 159

B C 160

B C 161

B C 162

A C 163

B C 164

A C 165

B D 166

B C 167

B C 168

A C 169

A C 170

A C 171

B C 172

B C 173

A C 174

B D 175

A C 176

A C 177

B C 178

A B 179

A C 180

B C 181

B C 182

B C 183

B C 184

B C 185

A C 186

A C 187

A C 188

A C 189

B C 190

A C 191

B C 192

A C 193

A C 194

B C 195

A C 196

B C 197

B C 198

B C 199

A C 200

B C 201

B C 202

A C 203

B C 204

A C 205

B C 206

A C 207

A C 208

B C 209

B C 210

A C 211

B C 212

B C 213

A C 214

B C 215

B C 216

B C 217

B C 218

A C 219

A D 220

A C 221

B C 222

A C 223

A C 224

A C 225

B C 226

B C 227

B C 228

B C 229

A C 230

A C 231

B C 232

A C 233

B C 234

B C 235

A C 236

B C 237

B C 238

A C 239

A C 240

A C 241

B C 242

B C 243

B C 244

B C 245

B C 246

A C 247

B C 248

B C 249

B C 250

A C 251

A C 252

A C 253

A C 254

A C 255

A C 256

B C 257

B C 258

B C 259

A C 260

B C 261

B C 262

B C 263

A C 264

B C 265

A C 266

B C 267

A C 268

B C 269

C C 270

B C 271

B C 272

B C 273

B C 274

B C 275

A C 276

B C 277

B C 278

A C 279

B C 280

A C 281

B C 282

A C 283

B C 284

A C 285

A C 286

A C 287

A C 288

A C 289

B C 290

A C 291

A C 292

A C 293

B C 294

B C 295

B C 296

C C 297

B C 298

B C 299

A C 300

A C 301

A C 302

A C 303

B C 304

B C 305

A C 306

B C 307

B C 308

A C 309

A C 310

B C 311

A C 312

B C 313

B C 314

B C 315

B C 316

B C 317

B C

Compounds 16, 20, 101, 104, and 123 were at least 10 times, but lessthan 25 times, more potent against the D816V mutant than against thewild-type Kit.

Compounds 17, 18, 19, 81, 156, 243, 277, and 296 were at least 25 times,but less than 50 times, more potent against the D816V mutant thanagainst the wild-type Kit.

Compounds 5, 37, 41, 43, 57, 78, 107, 114, 120, 182, 225, 227, and 269were at least 50 times, but less than 100 times, more potent against theD816V mutant than against the wild-type Kit.

Compounds 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 13, 14, 15, 24, 26, 28, 30,32, 35, 36, 38, 40, 42, 44, 48, 51, 55, 58, 59, 62, 64, 66, 68, 69, 70,71, 72, 73, 75, 76, 79, 82, 84, 86, 88, 90, 91, 93, 94, 97, 98, 99, 100,102, 106, 108, 110, 111, 112, 118, 119, 124, 128, 129, 139, 141, 145,148, 149, 150, 152, 153, 159, 161, 166, 167, 168, 171, 172, 174, 177,178, 180, 181, 186, 187, 194, 197, 200, 203, 205, 208, 214, 215, 216,221, 228, 231, 233, 236, 241, 242, 244, 247, 248, 249, 250, 251, 256,257, 258, 243, 259, 262, 264, 268, 270, 271, 272, 273, 275, 276, 279,280, 281, 282, 283, 293, 294, 295, 297, 298, 304, 306, 307, 308, 310,312, 313, 314, 315, and 317 were at least 100 times, but less than 500times, more potent against the D816V mutant than against the wild-typeKit.

Compounds 27, 31, 34, 39, 49, 50, 53, 54, 60, 63, 65, 67, 87, 95, 96,113, 117, 122, 130, 131, 135, 136, 137, 138, 140, 142, 143, 144, 147,160, 163, 170, 183, 189, 191, 196, 198, 201, 204, 209, 211, 212, 217,222, 226, 232, 234, 237, 245, 253, 254, 255, 260, 261, 266, 274, 278,284, 285, 289, 299, 300, 303, and 316 were at least 500 times, but lessthan 1000 times, more potent against the D816V mutant than against thewild-type Kit.

Compounds 12, 21, 22, 23, 25, 29, 33, 45, 47, 52, 56, 61, 74, 77, 80,83, 85, 89, 92, 103, 105, 109, 115, 116, 121, 125, 126, 127, 132, 133,134, 146, 151, 154, 155, 157, 158, 162, 164, 165, 169, 173, 175, 176,179, 184, 185, 188, 190, 192, 193, 195, 199, 202, 206, 207, 210, 213,218, 219, 220, 223, 224, 229, 230, 235, 238, 239, 240, 246, 252, 263,265, 267, 286, 287, 288, 290, 291, 292, 301, 302, 305, 309, and 311 weregreater than 1000 times more potent against the D816V mutant thanagainst the wild-type Kit.

Cellular Activity

HMC1.2 Autophosphorylation Assay:

10,000 HMC1.2 cells were incubated in 22 ul culture media (phenol-redfree IMDM, no serum) in each well of a 384-well plate and serum starvedovernight in a tissue culture incubator (5% CO₂, 37° C.). A 10-pointdose concentration series of compound (25 uM-95.4 pM) were then added tothe cells in a volume of 3.1 ul to each well (0.25% DMSO finalconcentration). After 90 minutes, 6 ul of 5× AlphaLISA Lysis Buffer(Perkin Elmer) supplemented with a protease and phosphatase inhibitorcocktail (Cell Signaling Technologies) was added to each well and shakenat 450 rpm for 15 minutes at 4° C. 10 ul of phospho-Y719 c-Kit and totalc-Kit antibodies (15 nM final concentration, Cell SignalingTechnologies) and 50 ug/ml AlphaLISA rabbit acceptor beads (PerkinElmer) were added to each well and shaken at 300 rpm at room temperaturefor 2 hours. 10 ul of 100 ug/ml streptavidin donor beads (Perkin Elmer)were added to each well, blocked from light with aluminum adhesive andshaken at 300 rpm at room temperature for 2 hours. Fluorescence signalwas obtained on Envision (Perkin Elmer) by AlphaScreen 384 well HTSprotocol. Data was normalized to 0% and 100% inhibition controls and theIC50 was calculated using Four Parameter Logistic IC50 curve fitting.

The Table below shows the activity of compounds in a Mast cell leukemiacell line, HMC 1.2. This cell line contains Kit mutated at positionsV560G and D816V resulting in constitutive activation of the kinase. Thefollowing compounds were tested in an assay to measure direct inhibitionof Kit D816V kinase activity by assaying Kit autophosphorylation attyrosine 719 on the Kit protein.

In the Table below, the following designations are used: <10 nM=A;10.01-100 nM=B; 100.01-1000 nM=C; 1000-10000 nM=D, >10000.01 nM=E; andND=not determined.

Inhibition of Compound Phosphorylation Number IC₅₀ (nM) 1 C 2 B 3 B 4 C5 B 6 B 7 C 8 C 9 C 10 A 11 B 12 B 13 C 14 B 15 B 16 C 17 B 18 B 19 C 20C 21 B 22 B 23 B 24 B 25 B 26 B 27 C 28 B 29 B 30 C 31 C 32 C 33 B 34 B35 B 36 B 37 C 38 B 39 B 40 C 41 C 42 C 43 B 44 C 45 B 46 B 47 A 48 B 49A 50 B 51 C 52 C 53 C 54 A 55 C 56 B 57 B 58 C 59 C 60 B 61 B 62 C 63 B64 C 65 C 66 C 67 B 68 C 69 B 70 C 71 C 72 C 73 B 74 B 75 C 76 B 77 B 78C 79 A 80 B 81 C 82 C 83 C 84 B 85 A 86 C 87 B 88 B 89 B 90 B 91 C 92 B93 A 94 B 95 B 96 C 97 C 98 C 99 B 100 C 101 C 102 C 103 C 104 C 105 B106 B 107 A 108 A 109 B 110 C 111 A 112 C 113 B 114 C 115 B 116 B 117 A118 B 119 B 120 B 121 B 122 ND 123 C 124 B 125 A 126 A 127 B 128 B 129 C130 B 131 B 132 B 133 B 134 A 135 B 136 B 137 B 138 B 139 C 140 C 141 C142 C 143 B 144 B 145 B 146 B 147 B 148 C 149 C 150 C 151 B 152 C 153 B154 B 155 B 156 B 157 B 158 A 159 B 160 B 161 B 162 A 163 C 164 B 165 B166 B 167 C 168 B 169 A 170 A 171 B 172 C 173 A 174 C 175 B 176 A 177 C178 B 179 B 180 C 181 C 182 C 183 B 184 B 185 A 186 B 187 B 188 A 189 B190 A 191 C 192 C 193 B 194 B 195 B 196 B 197 B 198 B 199 B 200 C 201 C202 C 203 B 204 B 205 B 206 B 207 A 208 C 209 C 210 A 211 A 212 B 213 A214 B 215 B 216 B 217 B 218 C 219 C 220 B 221 B 222 B 223 A 224 A 225 C226 B 227 C 228 B 229 A 230 B 231 B 232 B 233 C 234 C 235 B 236 B 237 B238 B 239 B 240 B 241 B 242 B 243 C 244 C 245 B 246 B 247 C 248 B 249 B250 B 251 B 252 A 253 B 254 B 255 B 256 B 257 C 258 C 259 B 260 C 261 B262 C 263 B 264 B 265 A 266 B 267 A 268 B 269 C 270 B 271 B 272 C 273 C274 B 275 B 276 B 277 B 278 B 279 C 280 B 281 B 282 B 283 B 284 B 285 A286 B 287 A 288 A 289 B 290 A 291 B 292 B 293 B 294 C 295 B 296 C 297 B298 B 299 B 300 B 301 B 302 B 303 B 304 C 305 B 306 B 307 C 308 B 309 B310 B 311 B 312 B 313 B 314 B 315 B 316 B 317 B

INCORPORATION BY REFERENCE

All publications and patents mentioned herein are hereby incorporated byreference in their entirety as if each individual publication or patentwas specifically and individually indicated to be incorporated byreference.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

We claim:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: X is selectedfrom CH or N; L is a bond, —(CR^(c)R^(c))_(n)—,—(CR^(c)R^(c))_(n)NR^(b)—, —NR^(b)(CR^(c)R^(c))_(n)—, —S(O)₂—, —S(O)—,—C(O)—, —OC(O)—, —C(O)O—, —(CR^(c)R^(c))_(n)—OC(O)—,—OC(O)—(CR^(c)R^(c))_(n)—, —(CR^(c)R^(c))_(n)—C(O)—,—C(O)—(CR^(c)R^(c))_(n)—, —NR^(b)C(O)(CR^(c)R^(c)),—C(O)NR^(b)—(CR^(c)R^(c)), where the two R^(c)'s, together with thecarbon to which they are attached, can form a carbocycle,—C(O)NR^(b)—(CR^(c)R^(b)), —(CR^(c)R^(c))—NR^(b)—(CR^(c)R^(c)),—NR^(b)C(S)—, —C(S)NR^(b)—, —NR^(b)C(O)—, —C(O)NR^(b)—, —NR^(b) S(O)₂, -or —S(O)₂NR^(b)—; R¹ is alkyl, carbocyclyl, carbocyclylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyleach of which is substituted with 0-5 occurrences of R^(d); R² is H,halo, aryl, alkenyl, heteroaryl, carbocyclyl, or heterocyclyl, whereineach of aryl, alkenyl, heteroaryl, carbocyclyl, and heterocyclyl issubstituted with 0-5 occurrences of R^(d); R³ is H, alkyl, heteroalkyl,haloalkyl, haloalkoxyl, —OR^(c), —C(O)OR^(c), —C(O)NR^(a)R^(b),—(CR^(c)R^(c))—NR^(b)—(CR^(c)R^(c))—H, —NR^(a)R^(b), or cyano, whereineach of alkyl, heteroalkyl, haloalkyl, and haloalkoxyl is substitutedwith 0-5 occurrences of R^(d); R^(a) and R^(b) are each independently H,alkyl, heteroalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, orheterocyclylalkyl, wherein each of alkyl, heteroalkyl, aryl, aralkyl,heterocyclyl, and heterocyclylalkyl is substituted with 0-5 occurrencesof R^(d); or R^(a) and R^(b) together with the nitrogen atom to whichthey are attached form a heterocyclyl substituted with 0-5 occurrencesof R^(d); R^(c) is H or alkyl; each R^(d) is independently halo,heteroalkyl, haloalkyl, haloalkoxyl, alkyl, alkynyl, hydroxyalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heteroaryl, heterocyclyl,heterocyclylalkyl, nitro, cyano, hydroxyl, —C(O)R^(a1), —OC(O)R^(a1),—C(O)OR^(a1), —SR^(a1), —S(O)₂R^(a1), —NR^(a1)R^(b1),—C(O)NR^(a1)R^(b1), —NR^(a1)S(O)₂R^(a1), or —OR^(a1); wherein each ofheteroalkyl, haloalkyl, haloalkoxyl, alkyl, alkynyl, hydroxyalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heteroaryl, heterocyclyl,and heterocyclylalkyl is substituted with 0-5 occurrences of R^(c1); ortwo R^(d) together with the atoms to which they are attached form acarbocyclyl or heterocyclyl, each optionally substituted with halo oralkyl; R^(a1) and R^(b1) are each independently H, alkyl, aralkyl,carbocyclyl, heteroaryl, or heterocyclyl; or R^(a1) and R^(b1) togetherwith the nitrogen atom to which they are attached form a heterocyclyloptionally substituted with halo or alkyl; each R^(c1) is independentlyhalo, —OR^(c2), —NR^(a1)R^(b1), alkyl, cyano, heteroalkyl, haloalkyl,haloalkoxyl, carbocyclyl, carbocyclylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroaralkyl, aryl, or aralkyl; R^(c2)is H or alkyl; p and r are each independently 1 or 2; and n is 1, 2, 3or
 4. 2. The compound of claim 1, wherein L is a bond,—(CR^(c)R^(c))_(n)—, —(CR^(c)R^(c))_(n)NR^(b)—,—NR^(b)(CR^(c)R^(c))_(n)—, —(CR^(c)R^(c))_(n)—C(O)—,—C(O)—(CR^(c)R^(c))_(n)—, —C(O)NR^(b)—(CR^(c)R^(c)), where the two Rc's,together with the C to which they are attached, can form a carbocycle,—C(O)NR^(b)—(CR^(c)R^(b)), —(CR^(c)R^(c))—NR^(b)—(CR^(c)R^(c)),—NR^(b)C(O)—, —C(O)NR^(b)—, - or —S(O)₂NR^(b)—.
 3. The compound of claim1, wherein L is —(CR^(c)R^(c))_(n)NR^(b)—, —NR^(b)(CR^(c)R^(c))_(n)—,—NR^(b)C(O)—, or —C(O)NR^(b)—.
 4. The compound of claim 1, wherein R¹ isaryl, carbocyclyl, carbocyclylalkyl, heterocyclyl, or heterocyclylalkyl,each of which is substituted with 0-5 occurrences of R^(d).
 5. Thecompound of claim 1, wherein R² is alkenyl, aryl, carbocyclyl,heteroaryl, or heterocyclyl, each of which is substituted with 0-5occurrences of R^(d).
 6. The compound of claim 1, wherein R² is a 5- or6-membered heterocyclyl substituted with 0-5 occurrences of R^(d). 7.The compound of claim 1, wherein R² is a 5- or 6-membered heteroarylsubstituted with 0-5 occurrences of R^(d).
 8. The compound of claim 1,wherein R² is selected from pyrrolyl, imidazolyl, pyrazolyl, pyridinyl,pyrimidinyl, thiophenyl, isoxazolyl, phenyl, dihydropyranyl, andtetrahydropyridinyl, each optionally substituted with 0-5 occurrences ofR^(d).
 9. The compound of claim 1, wherein R³ is H, alkyl, —OR′, or—NR^(a)R^(b).
 10. The compound of claim 1, wherein each R^(d) isindependently selected from halo, alkyl, carbocyclyl, carbocyclylalkyl,heterocyclyl, heterocyclylalkyl, nitro, cyano, hydroxyl, —C(O)R^(a1),—C(O)OR^(a1), —S(O)₂R^(a1), —NR^(a1)R^(b1), —C(O) NR^(a1)R^(b1), and—OR^(a1); wherein each of alkyl, carbocyclyl, carbocyclylalkyl,heterocyclyl, heterocyclylalkyl is substituted with 0-5 occurrences ofR^(c1); or two R^(d) together with the atoms to which they are attachedform a carbocyclyl or heterocyclyl, each optionally substituted withhalo or alkyl.
 11. The compound of claim 1, wherein p is 1 and r is 1.12. The compound of claim 1, wherein the compound is a compound ofFormula II:

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim1, wherein the compound is a compound of Formula III:

or a pharmaceutically acceptable salt thereof.
 14. The compound of claim1, wherein the compound is a compound of Formula IV:

or a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition comprising a compound of claim 1 or a pharmaceuticallyacceptable salt thereof.
 16. A method of treating mastocytosiscomprising administering to a patient a therapeutically effective amountof a compound of claim
 1. 17. A method of treating gastrointestinalstromal tumor, the method comprising administering to a patient atherapeutically effective amount of a compound of claim
 1. 18. A methodof treating acute myeloid leukemia, the method comprising administeringto a patient a therapeutically effective amount of a compound ofclaim
 1. 19. A method of treating melanoma, the method comprisingadministering to a patient a therapeutically effective amount of acompound of claim
 1. 20. A method of treating seminoma, the methodcomprising administering to a patient a therapeutically effective amountof a compound of claim
 1. 21. A method of treating a condition mediatedby mutant Kit, wherein said Kit is mutated at residue D816, the methodcomprising administering to a patient a therapeutically effective amountof a compound of claim 1.